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CN104447740B - Imidazolone derivative as well as drug composition and application thereof - Google Patents

Imidazolone derivative as well as drug composition and application thereof Download PDF

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CN104447740B
CN104447740B CN201410647871.2A CN201410647871A CN104447740B CN 104447740 B CN104447740 B CN 104447740B CN 201410647871 A CN201410647871 A CN 201410647871A CN 104447740 B CN104447740 B CN 104447740B
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methyl
imidazo
quinolin
pyridin
pyrazol
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CN104447740A (en
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张兴民
季奇
王磊
高聪敏
王恩思
杜镇建
巩龙龙
陈博
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BEIJING FORELAND BIOPHARMA Co Ltd
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Abstract

The application relates to an imidazolone compound and pharmaceutically acceptable salt, solvate, polymorphs or prodrugs thereof and also relates to a drug composition comprising the substances and application of the drug composition to prevention and treatment of protein kinase related diseases, such as cancers, metabolic diseases and cardiovascular diseases.

Description

Imidazolone derivatives, pharmaceutical compositions and uses thereof
Technical Field
The application belongs to the field of medicines, and relates to a series of imidazolone compounds, pharmaceutically acceptable salts, stereoisomers, isotopic labels, solvates, polymorphs or prodrugs thereof, pharmaceutical compositions containing the compounds and application of the compounds in treating diseases related to protein kinase activity, such as cancers, metabolic diseases, cardiovascular diseases and the like.
Background
Mammalian target of rapamycin (mTOR), a typical serine/threonine protein kinase, belongs to the phosphatidylinositol-3 kinase (PI 3K) related kinase family members, and is a major signaling molecule for cellular functions such as intracellular synthesis and catabolism. mTOR signaling pathways are closely related to nutrition, energy status and growth factors. It regulates a number of cellular processes including autophagy, protein, lipid, lysosomal synthesis and energy metabolism, cytoskeletal organization, cell survival, and the like. mTOR regulates the switch of anabolism and catabolism under changing mammalian cell peripheral nutritional conditions, thereby enabling cells to grow and survive under different nutritional conditions. Due to the important role of mTOR in cells, aberrant or deregulated mTOR signaling can lead to the development of human diseases (e.g., diseases such as cancer). Therefore, the mTOR signaling pathway is becoming an important target for designing anticancer drugs.
The PI3K/Akt/mTOR signal pathway activation is closely related to the occurrence of various tumors, and mTOR can accelerate the cell cycle, reduce apoptosis and promote the migration of tumor cells in brain glioma, breast cancer and ovarian cancer. Activation of mTOR initiates with growth factor receptors on the surface of some cells that are activated by ligands, such as epidermal growth factor receptor and insulin-like growth factors 1 and-2 (IGF-1 and-2). Activation of the receptor results in activation of PI3K kinase, which in turn results in activation of downstream effector Akt proteins. Akt is a regulatory factor that regulates cell survival at multiple levels. Phosphorylation of Akt inhibits the downstream TSC1/2 complex, resulting in activation of mTOR by Rheb. Downstream of the signaling pathways for PI3K/Akt and PEN/Akt and Ras/Erk1/2, the TSC1/2 complex plays a critical role in regulating mTOR activation.
It has now been found that two different mTOR protein complexes, mTORC1 and mTORC2, exist within the cell. These two protein complexes comprise unique proteins that interact with mTOR and are each regulated by different mechanisms. Significant progress has been made in the development of mTOR inhibitor drugs. Rapamycin was the first mTOR inhibitor discovered and showed better cancer inhibitory effects in various cancer models. Although rapamycin analogues with better pharmacological properties have been developed, clinically useful rapamycin analogues are limited to a few cancers. Akt is an important kinase for cancer cell survival, and mTORC2 can directly phosphorylate Akt, which provides a new idea for the research of mTORC2 on anticancer aspect, and promotes the research and development of second generation anticancer drugs simultaneously acting on two targets of mTORC1 and mTORC 2. Simultaneous inhibition of the activity of both mTOR complexes (mTORC1 and mTORC2) in cancer cells has a broader and more potent anticancer effect.
mTORC1 has six subunits and mTORC2 consists of seven subunits. Wherein the mTOR, mLST8, DEPTOR, and Tti1/Tel2 catalytic subunits are present in the mTORC1 and mTORC2 complex. While the two complexes have different regulatory proteins, Raptor and PRAS40 are present in mTORC1 and rictor, mSin and promoter 1/2 are present in mTORC 2. The upstream signal of mTORC1 comes mainly from intracellular and extracellular pathways including growth factors, cellular emergencies, energy states, oxygen and amino acids. These signals control many major processes in the cell, including protein, mRNA, lipid synthesis and autophagy. The heterodimer (TSC1/TSC2) is a key upstream regulator of mTORC1 and its function is an activator of Rheb GTPase. Binding of GTP to Rheb directly acts with mTORC1 and activates its enzymatic activity. As a GTPase activating protein for Rheb, TSC1/2 converts Rheb into an inactive and GDP-binding state by negative regulation. mTORC1 activates its downstream factors 4E-BP1 and S6K1 through phosphorylation to promote protein expression and increase mRNA production. In addition, mTORC1 also controls cellular metabolism and ATP production by interacting with SREBP1/2 transcription factor and HIF 1-alpha. In addition to its anabolic role, mTORC1 can also regulate autophagy with negative regulation to promote cell growth. In mammals, mTORC1 directly phosphorylates the ULK1/Atg13/FIP20 kinase complex and inhibits the initiation of autophagy. mTORC1 may also affect autophagy through other mechanisms, such as the regulation of inhibitors of autophagy, DAP1, and the promotion of formation of disassembly.
The signal path of mTORC2 is less understood than mTORC 1. mTORC2 signaling is not sensitive to nutritional conditions but responds to some growth factors, mTORC2 regulates several members of the AGC kinase subfamily, such as Akt, SGK1, and PKC- α. Akt activates downstream signaling proteins to regulate cell metabolism, survival, apoptosis, growth and proliferation. mTORC2 activates its function by directly phosphorylating the Akt (Ser473) site. But phosphorylation of TSC2 and GSK3- β was not affected in the absence of mTORC 2. mTORC2 also directly activates SGK1 kinase to regulate ion transfer and cell growth. But the function of SGK1 was completely inhibited without mTORC2 compared to Akt. Activation of PKC- α by mTORC2 can affect actin scaffold formation.
Many studies have shown that the mTOR signaling pathway is involved in the development of cancer. There are many compositional variations in cancer between downstream of PI3K and upstream of mTORC, including Tsc1/2, Lkb1, Pten, and Nf 1. Oncogene activation of mTOR induces several cancer cell growth, survival and proliferation processes. More and more studies are directed to the association of uncontrolled protein expression with mTORC 1. Because 4E-BP1/eIF4 downstream of mTORC1 plays a key role in tumor formation. 4E-BP1/eIF4 transmits oncogenic signals from Akt for mRNA expression that result in the expression of several specific oncogenic proteins that, in turn, ultimately regulate cell survival, cell cycle, neovascularization, energy metabolism, and tumor metastasis. In addition, ribosome synthesis associated with mTOR activation may be associated with high levels of cell growth.
Increased lipid synthesis is an important marker for tumor cell proliferation. This is due to the production of fatty acids required by novacells to synthesize cell membranes. The PI3K signaling pathway activates lipotropic synthesis factor (SREBP1), while mTORC1 is the signaling factor for PI3K to activate SREBP 1. Meanwhile, SREBP1 also drives the expression of several pentose phosphate oxidation constitutive factors, and the pentose phosphate oxidation pathway controls lipid synthesis and nucleic acid synthesis.
Continued activation of PI3K/mTORC1 signaling strongly inhibited autophagy. Inhibition of autophagy is detrimental to tumor cells by reducing their viability in the absence of nutrients and energy, thereby affecting tumor formation.
mTORC2 has been shown to potentially control the formation of vasculature and immune chemotaxis. This suggests that inhibition of mTORC2 may attenuate tumor formation and sustained growth by preventing neovascularization or reducing immune cell invasion. In some tumors, high expression of mTORC2 is associated with high expression of its subunit rictor. In mice, deletion of the tumor suppressor PTEN resulted in an increase in TORC2 function. These results support the important role of mTORC2 in tumor formation, while also suggesting that reducing mTORC2 activity is likely to be of great significance in anticancer therapy.
SUMMARY
The application provides a series of imidazolone derivatives which can be used for preparing medicines for treating diseases related to the activity of protein kinase.
According to one aspect of the present application, there is provided a compound represented by formula I, a pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polymorph or prodrug thereof:
wherein,
ring a and ring B are independently selected from aryl or heteroaryl, wherein heteroaryl contains at least one heteroatom selected from N, O, S;
ring C is a saturated carbocyclic ring or a saturated heterocyclic ring containing at least one heteroatom selected from N, O and S;
R1is at least one group connecting ring C (ring C is a saturated heterocyclic ring) selected from H; c optionally substituted by at least one group selected from halogen, cyano, amino, hydroxy, carboxy, trifluoromethyl and monocyclic or bicyclic aryl1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyl or C2-6An alkynyl group; or is selected from R6CO、R6SO2、R6SO, wherein, R6Is selected from NH2、NHR7(ii) a C optionally substituted with at least one of hydroxy, mercapto, amino, trifluoromethyl and halogen1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyl or C2-6An alkynyl group; monocyclic or bicyclic cycloalkyl (e.g., C1-6 cycloalkyl); a saturated or unsaturated mono-or bis-heterocyclyl group containing at least one heteroatom selected from N, O and S; a monocyclic or bicyclic aryl group; or a monocyclic or bicyclic heteroaryl group containing at least one heteroatom selected from N, O and an S atom (e.g., a monocyclic heteroaryl group containing 1 to 3 nitrogen atoms); said aryl or heteroaryl being optionally substituted by halogen, C1-6Alkyl substitution; and R is7Is selected from C1-6Alkyl radical, C2-6Alkenyl or C2-6Alkynyl, monocyclic or bicyclic aryl or heteroaryl;
ring C is a "saturated carbocyclic ring to which a heteroatom is attached" meaning that the saturated carbocyclic ring is substituted with a substituent containing a heteroatom. The substituent containing a hetero atom is selected from hydroxyl, sulfhydryl, amino, C connected with N, O or S1-6Alkyl radical, C2-6Alkenyl or C2-6Alkynyl (e.g. asAlkoxy, monoalkylamino, dialkylamino, alkylthio), aryl (monocyclic or bicyclic aryl), carbocyclic (C)3-6Cycloalkyl), heteroaryl (monocyclic or bicyclic heteroaryl), heterocyclyl (monocyclic or bicyclic heterocyclyl); and the saturated carbocyclic ring is optionally further substituted with other substituents selected from C optionally substituted with at least one group selected from halogen, cyano, amino, hydroxy, carboxy, trifluoromethyl and monocyclic or bicyclic aryl1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyl or C2-6An alkynyl group;
R2selected from H, C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyl or C2-6An alkynyl group;
R3is at least one group connecting ring B, independently selected from H, C1-6Alkyl, halogen and C1-6At least one of alkoxy groups;
R4is at least one group connecting ring a independently selected from H; halogen; a hydroxyl group; an amino group; a cyano group; c optionally substituted by halogen1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyl radical, C2-6An alkynyl group; and monocyclic or bicyclic aryl or heteroaryl optionally substituted with halo;
x is selected from CH or N.
In some embodiments, in formula I, ring a and ring B are independently selected from monocyclic or bicyclic aryl or heteroaryl; ring C is selected from a saturated mono-or bi-heterocyclic ring containing 4 to 8 ring atoms (the heteroatom in the heterocyclic ring is, for example, one N atom), or a saturated mono-carbocyclic ring containing 4 to 7 ring atoms to which one heteroatom is attached (for example, the heteroatom is O or N).
In some embodiments, in formula I, ring a and ring B are independently selected from monocyclic heteroaryl where the heteroatom is a nitrogen atom, and ring C is selected from a saturated monocyclic ring containing 4-7 ring atoms where the heteroatom is O or N to which one heteroatom is attached or a saturated monocyclic heterocycle containing 4-7 ring atoms where the heteroatom is a nitrogen atom.
In some embodiments, in formula I, wherein ring C is selected from a saturated carbocyclic ring or a saturated mono-heterocyclic ring containing 5 to 6 ring atoms in which the heteroatom is a nitrogen atom.
In some embodiments, in formula I, ring a and ring B are independently selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, imidazole, pyrrole, pyrazole, triazole, tetrazole, or phenyl; ring C is selected from azetidinyl, 3-piperidinyl, 4-piperidinyl, 2-pyrrolinyl (2-pyrrolinyl), 3-pyrrolinyl (3-pyrrolinyl), indolinyl (indolinyl) or pyrazolinyl. For example, ring a is one of the following structures:
ring B is pyridyl.
In some embodiments, in formula I, at the group R1Wherein heteroaryl is selected from monocyclic heteroaryl containing at least one N atom; optionally substituted by halogen, C1-6Alkyl substituted C5-10A monocyclic or bicyclic aryl group; a 4-7 membered saturated monocyclic ring; optionally at least one C1-6An alkyl-substituted amino group; c optionally substituted by at least one halogen, hydroxy, amino group1-6An alkyl group.
In some embodiments, in formula I, when ring C is selected from heterocyclyl where the heteroatom is N, R is1To one N atom; or when ring C is selected from a saturated carbocyclic ring to which one heteroatom is attached, the heteroatom being N, R1Attached to one N atom.
In some embodiments, in formula I, the compound is the following:
1- (1- (2-hydroxyacetyl) piperidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- (1- (1H-1,2, 4-triazole-3-carbonyl) piperidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) piperidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- (1- ((S) -2-hydroxypropionyl) piperidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- (1- ((R) -2-hydroxypropionyl) piperidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- (1- (2-hydroxyacetyl) pyrrolidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- (1- (1H-1,2, 4-triazole-3-carbonyl) pyrrolidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1-methylpyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- (1-ethylpyrrolidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- (1-acetylpyrrolidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- (1-Benzylpyrrolidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- (1- ((4-chlorophenyl) sulfonyl) pyrrolidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1-p-toluenesulfonylpyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
3- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) pyrrolidine-1-sulfonamide
3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (2,2, 2-trifluoroacetyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- ((1r,4r) -4-hydroxycyclohexyl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- ((1s,4s) -4-hydroxycyclohexyl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- ((1s,4s) -4-hydroxycyclohexyl) -3-methyl-8- (6-phenylpyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- ((1s,4s) -4-hydroxycyclohexyl) -8- (6-methoxy-5-methylpyridin-3-yl) -3-methyl-1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- ((1s,4s) -4-hydroxycyclohexyl) -3-methyl-8- (1-phenyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- ((1s,4s) -4-hydroxycyclohexyl) -3-methyl-8- (6-methylpyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- ((1r,4r) -4-hydroxycyclohexyl) -3-methyl-8- (1-phenyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- ((1r,4r) -4-hydroxycyclohexyl) -8- (6-methoxy-5-methylpyridin-3-yl) -3-methyl-1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- ((1r,4r) -4-hydroxycyclohexyl) -3-methyl-8- (6-phenylpyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
8- (6-Aminopyridin-3-yl) 1- ((1s,4s) -4-hydroxycyclohexyl) -3-methyl-1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(R) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(S) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(S) -1- (1- (ethylsulfonyl) pyrrolidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(S) -3-methyl-1- (1- (methylsulfonyl) pyrrolidin-3-yl) -8- (6-phenylpyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) - (R) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) piperidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- (3-hydroxycyclohexyl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
N- ((1s,4s) -4- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) cyclohexanyl) acetamide
N- ((1s,4s) -4- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) cyclohexyl) methanesulfonamide
(1s,4s) -4- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) cyclohexanecarboxylic acid
3-deuterated methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) piperidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) piperidin-3-yl) -1H-imidazo [4,5-c ] [1,5] naphthyridin-2 (3H) -one
(S) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c ] [1,5] naphthyridin-2 (3H) -one
(S) -3-methyl-1- (1- (methylsulfonyl) pyrrolidin-3-yl) -8- (6-phenylpyridin-3-yl) -1H-imidazo [4,5-c ] [1,5] naphthyridin-2 (3H) -one
2-methyl-2- (4- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) phenyl) propionamide
2-methyl-2- (4- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) phenyl) propanoic acid
1- (3-Hydroxycyclopentyl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(S) -8- (6- (1H-1,2, 4-triazol-1-yl) pyridin-3-yl) -3-methyl-1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(S) -8- (6- (1H-pyrazol-1-yl) pyridin-3-yl) -3-methyl-1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(S) -3-methyl-8- (6- (1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(S) -8- (6- (1H-1,2, 3-triazol-1-yl) pyridin-3-yl) -3-methyl-1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(S) -3-methyl-8- (6- (1-methyl-1H-pyrazol-3-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(S) -3-methyl-8- (6- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(R) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) piperidin-3-yl) -1H-imidazo [4,5-c ] [1,5] naphthyridin-2 (3H) -one
(S) -3-methyl-8- (6- (1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c ] [1,5] naphthyridin-2 (3H) -one
1- ((1s,4s) -4-hydroxycyclohexyl) -3-methyl-8- (6- (1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(R) -1- (1- (ethylsulfonyl) piperidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(R) -1- (1- (cyclopropylsulfonyl) piperidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(R) -3- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) piperidine-1-sulfonamide
(R) -N-ethyl-3- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) piperidine-1-carboxamide
(R) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- ((trifluoromethyl) sulfonyl) piperidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- (4-hydroxy-4-methylcyclohexyl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(R) -3-methyl-8- (6- (1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) piperidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) piperidin-4-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
3-methyl-8- (6- (1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) piperidin-4-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
3-methyl-8- (6- (1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) -1- (8- (methylsulfonyl) -8-azabicyclo [3.2.1] octan-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (8- (methylsulfonyl) -8-azabicyclo [3.2.1] octan-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
N- (2- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) ethyl) methanesulfonamide
3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) azetidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one.
According to another aspect of the present application, there is provided a pharmaceutical composition comprising a compound described herein above, a pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polymorph or prodrug thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition includes, but is not limited to, oral dosage forms, parenteral dosage forms, topical dosage forms, and rectal dosage forms. In some embodiments, the pharmaceutical composition may be tablets, capsules, pills, powders, sustained release formulations, solutions and suspensions for oral administration, sterile solutions, suspensions or emulsions for parenteral injection, ointments or creams for topical use, or suppositories for rectal administration. In other embodiments, the pharmaceutical composition is in unit dosage form suitable for single administration of a precise dose. In other embodiments, the amount of the compound ranges from about 0.001mg/kg body weight/day to about 1000mg/kg body weight/day. In other embodiments, the amount of the compound ranges from about 0.5mg/kg body weight/day to about 50mg/kg body weight/day. In some embodiments, the amount of the compound is from about 0.001 g/day to about 7 g/day. In other embodiments, the amount of the compound is from about 0.002 g/day to about 6 g/day. In other embodiments, the amount of the compound is from about 0.005 g/day to about 5 g/day. In other embodiments, the amount of the compound is from about 0.01 g/day to about 5 g/day. In other embodiments, the amount of the compound is from about 0.02 g/day to about 5 g/day. In other embodiments, the amount of the compound is from about 0.05 g/day to about 2.5 g/day. In other embodiments, the amount of the compound is from about 0.1 g/day to about 1 g/day. In other embodiments, dosage levels below the lower limit of the aforesaid range may be more than adequate. In other embodiments, dosage levels above the upper limit of the range recited above may be desired. In some embodiments, the compound is administered in a single dose, once per day. In other embodiments, the compound is administered in multiple doses, more than once per day. In some embodiments, the compound is administered twice daily. In other embodiments, the compound is administered three times per day. In other embodiments, the compound is administered four times per day. In other embodiments, the compound is administered four or more times per day. In some embodiments, the subject to which the pharmaceutical composition is administered is a mammal. In other embodiments, the mammal is a human. In other embodiments, the pharmaceutical composition further comprises at least one therapeutic agent (i.e., formulated as a dosage form). In some embodiments, the pharmaceutical composition and the at least one therapeutic agent are each combined in separate dosage forms into a combination product, such as a kit of parts.
According to a further aspect of the present application there is provided the use of a compound as described herein above, a pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polymorph or prodrug thereof, in the manufacture of a medicament for the inhibition of one or both of mTOR and PI3K kinase.
According to a further aspect of the present application there is provided a compound as described above, a pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polymorph or prodrug thereof, for use in the inhibition of one or both of mTOR and PI3K kinase.
According to another aspect of the present application there is provided the use of a compound described herein, a pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polymorph or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a disease associated with protein kinase activity, for example by inhibition of one or both of mTOR and PI 3K.
According to a further aspect of the present application, there is provided a compound, a pharmaceutically acceptable salt, a stereoisomer, an isotopic label, a solvate, a polymorph or a prodrug thereof, as described above for use in the treatment or prevention of a disease associated with protein kinase activity.
According to another aspect of the present application, there is provided a method of modulating (e.g. down-regulating) the activity of a protein kinase, comprising contacting the protein kinase with an effective amount of a compound as described above, or a pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polymorph or prodrug thereof. The method can be used in vivo or in vitro. Preferably, the protein kinase is selected from at least one of mTOR and PI 3K.
According to another aspect of the present application, there is provided a method of treating a disease associated with protein kinase activity, the method comprising administering to a subject in need thereof an effective amount of a compound of the present application, or a pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polymorph or prodrug thereof. The subject may be a mammal, such as a human.
According to some embodiments of the present application, the disease associated with protein kinase activity described herein (e.g., a disease treated or prevented by inhibiting one or both of mTOR and PI3K) can be a tumor, such as leukemia, malignant lymphoma, multiple myeloma, gastrointestinal stromal tumor, colon cancer, rectal cancer, breast cancer, liver cancer, stomach cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, choriocarcinoma, lung cancer, kidney cancer, prostate cancer, bladder cancer, pancreatic cancer, glioblastoma, mast cell tumor, brain tumor, germ cell tumor, melanoma, sarcoma, including dermatofibrosarcoma protruberans, osteosarcoma. The diseases associated with protein kinase activity described herein may also be metabolic diseases (e.g. diabetes, obesity) and cardiovascular diseases (e.g. atherosclerosis).
Detailed description of the invention
The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals, and treatises, are hereby incorporated by reference in their entirety.
Chemical terminology
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are incorporated by reference in their entirety unless otherwise indicated. If there are multiple definitions of terms herein, the definition in this section controls.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the subject matter of the application. In this application, the use of the singular also includes the plural unless specifically stated otherwise. It should also be noted that the use of "or", "or" means "and/or" unless stated otherwise. Furthermore, the term "comprising" as well as other forms, such as "includes," "including," and "containing," are not limiting.
Can be found in the reference (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4)THED. "Vols.A (2000) and B (2001), Plenum Press, New York). Unless otherwise stated, conventional methods within the skill of the art are employed, such as mass spectrometry, NMR, IR and UV/VisSpectroscopic and pharmacological methods. Unless a specific definition is set forth, the terms used herein in the pertinent description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for use of the kit, or in a manner known in the art or as described herein. The techniques and methods described above can generally be practiced according to conventional methods well known in the art, as described in various general and more specific documents referred to and discussed in this specification. In the present specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds.
When a substituent is described by a general formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the formula is written from right to left. For example, CH2O is equivalent to OCH2。
Unless otherwise indicated, the use of general chemical terms such as, but not limited to, "alkyl", "amine", "aryl" is equivalent to their optionally substituted forms. For example, "alkyl" as used herein includes optionally substituted alkyl.
The terms "optionally/any" or "optionally/optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, an "optionally substituted alkyl" refers to an "unsubstituted alkyl" (alkyl unsubstituted by a substituent) or a "substituted alkyl" (alkyl substituted by a substituent), as defined below.
As used herein C1-CnComprising C1-C2、C1-C3、……C1-Cn. For example, the "C" is1-C4By "group" is meant a moiety having 1 to 4 carbon atoms in the moiety, i.e., the group contains 1 carbonAtom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, for example, "C1-C4Alkyl "means an alkyl group having 1 to 4 carbon atoms, i.e., the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Herein, a numerical range, such as "1 to 10" refers to each integer in the given range, such as "1 to 10 carbon atoms" means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.
The term "alkyl" as used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched chain saturated aliphatic hydrocarbon. The "alkyl" groups herein preferably may have from 1 to about 20 carbon atoms, for example from 1 to about 10 carbon atoms, from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms, or from 1 to about 4 carbon atoms or from 1 to about 3 carbon atoms. Examples of alkyl groups herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-dimethyl-l-butyl, 3-dimethyl-1-butyl, methyl, ethyl, n-propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl and hexyl, and longer alkyl groups such as heptyl and octyl, and the like. When a group as defined herein, such as "alkyl" appears in a numerical range, e.g. "C1-C6Alkyl "or" C1-6Alkyl "means an alkyl group that can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and the alkyl group herein also encompasses instances where no numerical range is specified.
"alkyl" as used herein in combination refers to alkyl groups linked to other groups, such as alkyl in alkoxy, alkyl in alkylthio, hydroxyalkyl, haloalkyl, cyanoalkyl, monoalkylamino, "alkyl" in dialkylamino, and the like.
The term "alkoxy" as used herein, alone or in combination, refers to an alkyl ether group (O-alkyl), non-limiting examples of which include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.
The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight or optionally substituted branched chain monovalent hydrocarbon radical having at least one C ═ C double bond. The alkenyl group has, but is not limited to, 2 to about 18 carbon atoms, for example, 2 to about 10 carbon atoms, or 2 to about 8 carbon atoms, 2 to about 6 carbon atoms, 2 to about 4 carbon atoms. The double bond in these groups may be in either the cis or trans conformation and should be understood to encompass both isomers. Examples include, but are not limited to, ethenyl (CH ═ CH)2) 1-propenyl (CH)2CH＝CH2) Isopropenyl (C (CH)3)＝CH2) Butenyl, 1, 3-butadienyl and the like. When a numerical range is present for alkenyl as defined herein, e.g. "C2-C6Alkenyl "or" C2-6The "alkenyl group" means an alkenyl group which may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, and the alkenyl group herein also covers the case where no numerical range is specified.
The term "alkynyl", as used herein, alone or in combination, refers to an optionally substituted straight or branched chain monovalent hydrocarbon radical having at least one C ≡ C triple bond. The alkynyl group has, but is not limited to, 2 to about 18 carbon atoms, for example it has 2 to about 10 carbon atoms, or has 2 to about 8 carbon atoms, or 2 to about 6 carbon atoms, or 2 to about 4 carbon atoms. Examples of alkynyl groups herein include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1, 3-butadiynyl, and the like. When a numerical range occurs for alkynyl as defined herein, for example "C2-C6Alkynyl "or" C2-6Alkynyl "refers to an alkynyl group that can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and alkynyl groups herein also encompass instances where no numerical range is specified.
The terms "halo" or "halogen substituted", as used herein, alone or in combination, refer to an optionally substituted group (e.g., alkyl, alkenyl, and alkynyl) wherein at least one hydrogen atom is replaced with a halogen (e.g., fluorine, chlorine, bromine, iodine, or a combination thereof). In some embodiments, two or more hydrogens are replaced with the same halogen as each other (e.g., difluoromethyl, trifluoromethyl); in other embodiments two or more hydrogens are replaced with halogens that are not exactly the same as each other (e.g., 1-chloro-1-fluoro-1-iodoethyl). Non-limiting examples of haloalkyl groups are fluoromethyl and bromoethyl. A non-limiting example of a haloalkenyl group is bromovinyl. A non-limiting example of a haloalkynyl group is a chloroethynyl group.
The term "aryl/aryl" as used herein, alone or in combination, refers to an optionally substituted aromatic hydrocarbon group having from 6 to about 20, such as 6 to 12 or 6 to 10 ring-forming carbon atoms, which may be a monocyclic aryl, bicyclic aryl or higher ring aryl. The bicyclic aryl or higher ring aryl may be a monocyclic aryl fused to other independent rings such as alicyclic, heterocyclic, aromatic ring, aromatic heterocyclic. Non-limiting examples of monocyclic aryl groups include monocyclic aryl groups of 6 to about 12, 6 to about 10, or 6 to about 8 ring-forming carbon atoms, such as phenyl; bicyclic aryl is for example naphthyl; polycyclic aryl radicals are, for example, phenanthryl, anthracyl, azulenyl.
The term "heteroaryl" as used herein, alone or in combination, refers to optionally substituted heteroaryl groups comprising from about 5 to about 20, such as from 5 to 12 or from 5 to 10, backbone ring-forming atoms, wherein at least one (e.g., 1-4, 1-3, 1-2) ring-forming atoms is a heteroatom independently selected from the group consisting of heteroatoms consisting of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but is not limited thereto. The ring of the group does not contain two adjacent O or S atoms. Heteroaryl includes monocyclic heteroaryl (having one ring), bicyclic heteroaryl (having two rings), or polycyclic heteroaryl (having more than two rings). In embodiments where two or more heteroatoms are present in the ring, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different from each other. The bicyclic heteroaryl or higher ring heteroaryl may be a monocyclic heteroaryl fused with other independent rings such as alicyclic ring, heterocyclic ring, aromatic heterocyclic ring (which may be collectively referred to as fused ring heteroaryl). Non-limiting examples of monocyclic heteroaryl groups include monocyclic heteroaryl groups of 5 to about 12, 5 to about 10, 5 to about 7, or 6 backbone ring atoms, for example, non-limiting examples of which include pyridyl; fused ring heteroaryls include benzimidazolyl (benzimidazolyl), quinolyl (quinolyl), and acridinyl (acridininyl). Other examples of heteroaryl groups include, but are not limited to: pyridine, pyrimidine, pyrazine, pyridazine, triazine, furan, thiophene, imidazole, triazole, tetrazole, thiazole, isothiazole, 1,2, 4-thiadiazole, pyrrole, pyrazole, oxazole, isoxazole, oxadiazole, benzofuran, benzothiophene, benzothiazole, indole, indazole, quinoline, isoquinoline, purine, carbazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine, pyrazolopyridine, pyrazolopyrimidine, and the like. Acridinyl, phenazinyl, benzoxazolyl, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, isoquinolyl, indolizinyl, isothiazolyl, isoindolinyl, oxadiazolyl, purinyl, phthalazinyl, pteridinyl, quinazolinyl, quinoxalinyl, triazinyl, thiadiazolyl, and the like, and oxides thereof, such as pyridyl-N-oxide (pyridyl-N-oxide), and the like.
The term "heterocycle" or "heterocyclyl" as used herein, alone or in combination, refers to a non-aromatic heterocycle, which includes saturated heterocycles or unsaturated heterocycles (containing unsaturation). Wherein one or more (e.g., 1-4, 1-3, 1-2) ring-forming atoms are heteroatoms, such as oxygen, nitrogen or sulfur atoms. Heterocycles can include mono-heterocycles (having one ring) or bis-heterocycles (having two bridged rings) or polyheterocycles (having more than two bridged rings); spiro rings are also included. A heterocyclyl group can have 3 to about 20 ring-forming atoms, such as 3 to about 10, 3 to about 8, 4 to 7, 5 to about 8, or 5 to about 6 ring-forming atoms. Non-limiting examples of heterocyclic groups include azinyl (azinyl), azetidinyl (azidinyl), oxetanyl (oxolanyl), thietanyl (thietanyl), homopiperidinyl (homopiperidinyl), oxypentanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl (1,2,3,6-tetrahydropyridinyl), 2-pyrrolinyl (2-pyrrolinyl), 3-pyrrolinyl (3-pyrrolinyl), indolinyl (indolinyl), 2H-pyranyl (2H-pyranyl), 4H-pyranyl (4H-pyranyl), dioxacyclohexyl (dioxanyl), 1,3-dioxolanyl (1,3-dioxolanyl), pyrazole (pyrazolinyl), cyclohexyl (dithiopyranyl), dithiopyranyl (dihydropyranyl), dithiopyranyl (dihydropyranyl), dithiopyranyl (dithiopyranyl), dithiopyranyl (dihydropyranyl), dithiopyranyl (dihydropyranyl), dithiopyranyl (dithiopyranyl), dithiopyranyl (dihydropyranyl), dithiopyranyl (dithiopyranyl, imidazolinyl (imidazolinyl), imidazolinyl (imidazolinidinyl), 3-azabicyclo [3.1.0] hexyl (3-azabicyclo [3.1.0] hexyl), 3-azabicyclo [4.1.0] heptyl (3-azabicyclo [4.1.0] hexyl), 3H-indolyl (3H-indolyl) and quinolyl (quinolizinyl), and the like. The term also includes all cyclic forms of saccharides, including but not limited to monosaccharides, disaccharides, and oligosaccharides. Examples also include, but are not limited to, aziridine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, oxazolidine, thiazolidine, imidazolidine, isoxazolidine, isothiazolidine, pyrazolidine, morpholine, thiomorpholine, piperazine, piperidinyl, and the like. Heterocyclic groups also include heterocycles having one or more aromatic rings fused (i.e., having a common bond), such as 2, 3-dihydrobenzofuran, 1, 3-benzodioxole, benzo-1, 4-dioxane, phthalimide, naphthalimide. The heterocyclic group having one or more aromatic condensed rings may be connected to other groups through an aromatic ring or a non-aromatic ring moiety. Other groups may be attached to the heterocycle via a heteroatom or carbon atom (i.e., the heterocycle is attached to the parent molecule or further substituted).
The term "carbocycle" or "carbocyclyl" as used herein, alone or in combination, refers to a non-aromatic carbon-containing ring, including saturated carbocycles (e.g., cycloalkyls) or unsaturated carbocycles (e.g., cycloalkenyls). Carbocycle includes monocyclic (having one ring), and may be, for example, monocyclic cycloalkyl; a bicyclic carbocycle (having two rings), for example, may be a bicyclic cycloalkyl; carbocyclic (having more than two rings). The rings may be bridged or spiro. Carbocycle (e.g., cycloalkyl or cycloalkenyl) can have 3 to 20 carbon atoms, for example, 3 to about 15 ring-forming carbon atoms or 3 to about 10 ring-forming carbon atoms or 3 to 6 ring-forming carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexadienyl, cycloheptatrienyl, adamantyl, and the like.
"halogen" means fluorine, chlorine, bromine, iodine. Fluorine, chlorine and bromine are preferred. Cyano means "-CN"; hydroxyl refers to "-OH"; mercapto means "-SH"; amino means-NH2”。
The term "substituted" means that one or more hydrogens on a given atom are replaced with the indicated group, and that the substitution results in a stable compound if the normal valency of the indicated atom is not exceeded under the circumstances at hand.
Pharmaceutical terms
Certain pharmaceutical terms as used herein with respect to the terms "subject", "patient" or "individual" refer to an individual suffering from a disease, disorder or condition, and the like, including mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment related to the methods and compositions provided herein, the mammal is a human.
As used herein, the term "treating" and other similar synonyms include alleviating, or ameliorating a symptom of a disease or disorder, preventing other symptoms, ameliorating, or preventing an underlying metabolic cause of a symptom, inhibiting a disease or disorder, e.g., arresting the development of a disease or disorder, alleviating a disease or disorder, ameliorating a disease or disorder, alleviating a symptom of a disease or disorder, or discontinuing a symptom of a disease or disorder, and further, the term encompasses prophylactic purposes. The term also includes obtaining a therapeutic effect and/or a prophylactic effect. The therapeutic effect refers to curing or ameliorating the underlying disease being treated. In addition, a cure or amelioration of one or more physiological symptoms associated with the underlying disease is also a therapeutic effect, e.g., an improvement in the condition of the patient is observed, although the patient may still be affected by the underlying disease. For prophylactic effect, the composition can be administered to a patient at risk of developing a particular disease, or to a patient presenting with one or more physiological symptoms of the disease, even if a diagnosis of the disease has not yet been made.
The terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein, refer to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is clinically necessary to provide a significant remission effect of the condition. An effective amount suitable in any individual case can be determined using techniques such as a dose escalation assay.
The terms "administering," "administration," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, via the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical and rectal administration. Administration techniques useful for the compounds and methods described herein are well known to those skilled in the art, for example, in Goodman and Gilman, the pharmacological Basis of Therapeutics, current ed.; pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
The term "acceptable" as used herein with respect to a formulation, composition or ingredient means that there is no long-term deleterious effect on the general health of the subject being treated.
The term "pharmaceutically acceptable" as used herein refers to a substance (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present application, and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting in an adverse manner with any of the components contained in the composition.
The term "pharmaceutical composition" as used herein refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical ingredient including, but not limited to, carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and/or excipients.
The term "carrier" as used herein refers to a relatively non-toxic chemical compound or agent that facilitates the introduction of the compound into a cell or tissue.
The term "pharmaceutically acceptable salt" as used herein refers to salts that retain the biological potency of the free acid and free base of the specified compound, and that are biologically or otherwise non-adverse. The compounds of the present application also include pharmaceutically acceptable salts. Pharmaceutically acceptable salts refer to the form in which the base group in the parent compound is converted to a salt. Pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amine (amino) groups. Pharmaceutically acceptable salts of the present application can be synthesized from the parent compound by reacting a basic group in the parent compound with 1-4 equivalents of an acid in a solvent system. Suitable salts are listed in Remingtong's Pharmaceutical sciences, 17thed., MackPublishing Company, Easton, Pa.,1985, p.1418 and Journal of Pharmaceutical Science,66,2 (1977).
Unless otherwise indicated, salts in this application refer to acid salts formed with organic/inorganic acids, as well as basic salts formed with organic/inorganic bases. In addition, when the basic functional group of the compound of formula I is pyridine or imidazole (but not limited to pyridine or imidazole) and the acidic functional group is carboxylic acid (but not limited to carboxylic acid), zwitterions (inner salts) are formed and are included in the salts herein.
The term "solvate" as used herein refers to a combination of a compound of the present application and a solvent molecule formed by solvation. In some instances, a solvate refers to a hydrate, i.e., the solvent molecule is a water molecule, and the combination of a compound of the present application and water forms a hydrate. One or more of the compounds of the present application may exist in solvated forms, as with pharmaceutically acceptable solvents such as water, ethanol, and the like, and thus, both solvated and unsolvated forms are encompassed by the present application. "solvate" refers to a physical aggregate of a compound of the present application with one or more solvent molecules, the physical aggregate including varying degrees of ionic and covalent bonding, such as hydrogen bonding. It has been shown that this solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystal. "solvate" includes both a solvent phase and an isolatable solvate moiety. Examples of corresponding solvates are numerous and include ethanol solvates, methanol solvates, and the like. "hydrate" is a compound of water (H)2O) the molecule is a solvate of the solvent.
One or more of the compounds of the present application may be optionally prepared as solvates. The preparation of solvates is well known. For example, M.Caira et al, J.pharmaceutical Sci, 93(3),601-611(2004) describe the preparation of solvates of the antifungal agent fluconazole, i.e., using ethyl acetate and water. Van binder et al, aapspharmcitech, 5(1), article 12 (2004); similar preparation of solvates, hydrates are also described in a.l. bingham et al, chem.commu., 603-604 (2001). A typical, non-limiting, preparation procedure is to dissolve the compound of the invention in the desired amount of the desired solvent (organic solvent or water or a mixture thereof) at a temperature above ambient temperature, cool it down, settle it for crystallization, and then isolate and pick out the crystals by standard methods. The presence of the solvent (water) forming the solvate (hydrate) in the crystallization can be confirmed by i.r. spectroscopic analysis technique.
The term "polymorph" or "polymorph" as used herein refers to a compound of the present application in different crystal lattice forms.
The term "isotopic label" as used herein refers to isotopically labeled compounds of the present application. For example, isotopes in the compounds of the present application include various isotopes of H, C, N, O, P, F, S, such as2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F and36S。
the term "pharmaceutically acceptable prodrug" as used herein refers to any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the present application which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present application or a pharmaceutically active metabolite or residue thereof. Particularly preferred derivatives or prodrugs are those compounds which, when administered to a patient, enhance the bioavailability of the compounds of the present application (e.g., may allow an orally administered compound to be more readily absorbed into the blood), or facilitate delivery of the parent compound to a biological organ or site of action (e.g., the brain or lymphatic system).
Various prodrug forms are well known in the art. See, Pro-drugs Novel Delivery Systems (1987) Vol.14 of the A.C.S.Symposis Series, Bioreproducible Carriers in Drug Design, (1987) Edward B.Roche, ed., American pharmaceutical Association, and in Pergamon Press, both by T.Higuchi and V.Stella, for a discussion of prodrugs. Design of produgs, Bundgaard, a.ed., Elseview,1985 and Method in Enzymology, Widder, k.et., ed.; academy, 1985, vol.42, p.309-396; bundgaard, H. "Design and Application of Prodrugs" in A Textbook of Drug Design and Development, Krosgaard-Larsen and H.Bundgaard, Ed.,1991, Chapter 113 and 191; and Bundgaard, h., Advanced Drug delivery review,1992,8,1-38, which are incorporated herein by reference.
"stereoisomers" as used herein refers to isomers resulting from the different arrangement of atoms in a molecule in space. The compounds of formula I contain asymmetric or chiral centers and, therefore, exist in different stereoisomeric forms. All stereostructures of formula I are as well as mixtures, including racemic mixtures, as part of the present application. Diastereomeric mixtures can be separated into the individual diastereomers, based on their different physicochemical properties, by well-known means, e.g., resolution of the enantiomers can be converted into the diastereomers by reaction with a suitable optically active substance (e.g., a chiral alcohol or Mosher's moylchloride), which can be separated and converted (e.g., hydrolyzed) into the corresponding individual isomers. Some of the compounds of formula 1 may be atropisomers (e.g., substituted aryl) are also part of this application. Enantiomers can also be separated using a chiral chromatography column. The compounds of formula I may exist in different tautomeric forms, all of which are intended to be encompassed by the present application. For example, keto-enol and imine-enamine forms of the compounds.
As used herein, "metabolic disease" refers to a disease caused by metabolic problems, including metabolic disorders and metabolic hyperactivity, and includes mainly the following diseases: diabetes, diabetic ketoacidosis, hyperglycemic hyperosmolar syndrome, hypoglycemia, gout, protein-energy malnutrition, vitamin A deficiency, scurvy, vitamin D deficiency, osteoporosis, etc.
As used herein, "cardiovascular disease" is also known as circulatory disease and is a series of diseases involving the circulatory system, which refers to the organs and tissues that transport blood in the human body, mainly including the heart, blood vessels (arteries, veins, microvessels), and can be subdivided into acute and chronic, and is generally associated with arteriosclerosis. Cardiovascular diseases include: heart disease, hypotension, hypertension, hyperglycemia, stroke, myocardial infarction, thrombosis, arteriosclerosis, etc.
Detailed Description
The claims hereof set forth the features of novelty that characterize the present application. The following sets forth exemplary embodiments that utilize the principles of the present application. The features and advantages of the present application may be better understood by reference to the following.
Although preferred embodiments of the present application are described herein, these embodiments are provided by way of example only. It is to be understood that variations of the embodiments of the present application described herein may also be used to implement the teachings of the present application. Those of ordinary skill in the art will appreciate that various modifications, changes, and substitutions can be made without departing from the scope of the present application. It should be understood that the scope of the various aspects of the application is defined by the claims and that methods and structures within the scope of these claims and their equivalents are intended to be covered by the claims.
Synthetic route
Methods for the synthesis of compounds of the present application include, but are not limited to, the following equations and reaction steps:
the LC-MS analysis conditions during the synthesis were as follows:
the instrument comprises the following steps: agilent LCMS1260/MSD6120
A chromatographic column: agilent SB-C18,2.1 x 50mm,1.8 μm, SN USWEY07289
Mobile phase: a is H20 (0.1% FA) 90%, B is ACN 10%, 0.400mL/min,45.00 deg.C
Time-table
The instrument parameters are as follows:
route one:
synthesis of intermediate 1:
70g of ice and 32g of NaOH were mixed, 15.4ml of nitromethane were slowly added with stirring, and the mixture was stirred at 0 ℃ for 1 hour. It is then poured into a mixture of 70g of ice and 72ml of 37% HCl and is ready for use. A2000 ml single-necked flask was charged with 50g of 2-amino-5-bromobenzoic acid, 300ml of water and 300ml of acetone, stirred, added with the stock solution, reacted at room temperature, and monitored by TLC. After the reaction, the solution was filtered and drained. This gave 150.25g of intermediate as a yellow solid in 76% yield.
Synthesis of intermediate 2:
50.25g (0.175mol) of intermediate 1 was placed in a 500ml single neck flask, 250ml of acetic anhydride was added, the temperature was raised to 60 ℃ and 18.2g (0.23mol) of potassium acetate was added. The temperature was raised to 110 ℃ for reaction and monitored by TLC. After 4h, cool to room temperature, filter, and wash with vinegar until colorless, yielding 226.8g of intermediate as a white solid in 56% yield.
Synthesis of intermediate 3:
26.8g (99mmol) of intermediate 2 are placed in a 500ml single-neck flask, 200ml of phosphorus oxychloride are added, reflux is carried out at 120 ℃ for 1h and monitoring by TLC. After the reaction is finished, pouring the mixture into a large amount of ice water, and stirring to separate out a precipitate. The mixture was filtered, and the filter cake was washed with ice water and dissolved in dichloromethane. The organic phase was washed three times with brine, dried over anhydrous magnesium sulfate and spin-dried to give intermediate 316.1g, 53% yield.
Intermediate 106: 3- ((6-bromo-3-nitroquinolin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester
After 9.8g (34.1mmol) of compound 3 and 11.3g (56.4mmol) of compound 105 were dissolved in 100ml of DCM and stirred to dissolve, 8.6ml (61.7mmol) of triethylamine was added and stirred at room temperature for 2 hours, TLC (PE: EA ═ 3:1) showed completion of the reaction. The reaction mixture was purified by silica gel column (petroleum ether: ethyl acetate: 1-ethyl acetate) to obtain 13.7g of yellow powder, and the yield was 88.5%. LC-MS 451,453[ M + 1]]+,tR＝2.696min.
Intermediate 107: 3- ((3-amino-6-bromoquinolin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester
Suspending 12.3g (27.25mmol) of intermediate 106 in 123ml DMF, adding 30.75g (136.27mmol) stannous chloride dihydrate in batches under the cooling of ice bath, removing the ice bath after the addition is finished, stirring for 1 hour at room temperature, TLC (ethyl acetate + triethylamine) shows that raw materials are completely reacted, pouring into 820ml saturated sodium bicarbonate, stirring and quenching, extracting with 400ml ethyl acetate, carrying out suction filtration on two phases, separating liquid, extracting the water phase with 2 × 200ml ethyl acetate, stirring the solid obtained by suction filtration with 2 × 200ml ethyl acetate, carrying out suction filtration, combining the filtrate with the organic phase, washing with 200ml saturated saline, drying, filtering, evaporating to dryness to obtain 13.3g of crude yellow solid, and obtaining crude product yield of crude product>100％。LC-MS:421,423[M+1]+,tR＝1.743min.
Intermediate 108: 3- (8-bromo-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) piperidine-1-carboxylic acid tert-butyl ester
2.09g of crude compound 107 (ca. 3.3mmol) are dissolved in 10ml of dichloromethane, cooled to 0 ℃ and 1.5ml (10.8mmol) of triethylamine are added, and the mixture is stirred dropwiseAdding 0.49g (1.65mmol) of triphosgene solution in 10ml of dichloromethane, stirring at 0-5 ℃ for 2 hours, TLC (ethyl acetate) shows that no raw material exists basically, adding 25ml of saturated sodium bicarbonate, quenching at 0 ℃, stirring for 10min, separating out an organic phase, extracting an aqueous phase with 3 × 20ml of dichloromethane, combining the organic phases, drying, filtering, evaporating to dryness, purifying by a silica gel column (ethyl acetate-ethyl acetate: methanol: 10:1) to obtain 1.29g of yellow powder, wherein the yield is 87.4 percent, LC-MS (liquid chromatography-Mass Spectrometry): 447,449[ M + 1%]+,tR＝2.203min.
Intermediate 109: 3- (8-bromo-3-methyl-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) piperidine-1-carboxylic acid tert-butyl ester
Suspending 2g (4.47mmol) of intermediate 108 in 50ml dichloromethane, adding 0.15g TBAB (0.45mmol) and 40ml 10% sodium hydroxide solution, adding 0.7ml (11.2mmol) iodomethane under stirring, stirring at room temperature for 20 hours, TLC (DCM: MeOH 10:1) indicating no raw material, separating, extracting the water layer with 2 × 20ml dichloromethane, combining the organic phases, drying, filtering and evaporating to dryness to obtain a crude product, purifying the crude product by silica gel column chromatography (dichloromethane: MeOH 50: 1-30: 1) to obtain 2.0g yellow powder, yield 97%. LC-MS:461,463[ M + 1: (M + 1): 97%. LC-MS:461,463]+,tR＝2.365min.
An intermediate 110: 3- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-hydro-1H-imidazo [4,5-c ] quinolin-1-yl) piperidine-1-carboxylic acid tert-butyl ester
1.55g (6.5mmol) of Compound 8A, 1.98g (7.8mmol) of pinacol diboron, 1.91g (19.5mmol) of potassium acetate and 0.212g (0.26mmol) of Pd (dppf) Cl under nitrogen2.CH2Cl2Suspended in 30ml dioxane, heated to 95 ℃ and stirred for 2 hours, TLC (ethyl acetate) showed reactionAnd (4) finishing. The crude reaction solution was cooled to room temperature and 2g (4.34mmol) of intermediate 109, 5.66g (17.36mmol) of cesium carbonate, 10ml of dioxane, 10ml of 2M sodium carbonate solution and 0.177g (0.22mmol) of Pd (dppf) Cl were added2.CH2Cl2Heating to 110 ℃ and stirring for 5 hours, TLC (DCM: MeOH 10:1) shows completion of the reaction, cooling, distilling off dioxane, dissolving in 60ml dichloromethane and 60ml water, separating out the organic phase, extracting the aqueous phase with 60ml dichloromethane, combining the organic phases, drying, evaporating to dryness, purifying with silica gel column (dichloromethane: MeOH 30: 1-10: 1) to obtain 2g of earth powder with 85% yield. LC-MS 540[ M + 1]]+,tR＝2.148min.
Intermediate 111: 3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (piperidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1g (1.87mmol) of compound 110 are dissolved in 30ml of dichloromethane and, with stirring, dried hydrogen chloride gas is passed through for 5h, a large amount of precipitate appears, TLC (DCM: MeOH ═ 10:1) shows completion of the reaction, suction filtration is carried out, and 1.34g of the crude hydrochloride are dried in vacuo in crude yield>100％。LC-MS:440[M+1]+,tR＝1.427min.
Example 1: 1- (1- (2-hydroxyacetyl) piperidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazole-4-) Yl) pyridin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
20mg (0.0455mmol) of compound 111, 4.15mg (0.0546mmol) of glycolic acid, 9.23mg (0.0683mmol) of HOBt and 13.09mg of EDCI (0.0683mmol) are suspended in 2ml of dichloromethane, 13.9mg (0.137mmol) of triethylamine are added, stirring is carried out at room temperature for 5 hours, TLC (DCM: MeOH ═ 10:1) after completion of the reaction of the starting materials, 5ml of saturated sodium bicarbonate solution was added thereto and stirred for 0.5 hour, the organic phase was separated, the aqueous phase was extracted with 2 × 5ml of dichloromethane, the organic phases were combined, dried and evaporated to dryness, and preparative TLC purification (dichloromethane: methanol ═ 10:1) was carried out to give the title compound of example 1 as 14mg of a pale yellow powder with a yield of 61.8%. LC-MS:498[ M + 1:]+,tR＝1.436min.1H NMR(400MHz,CDCl3)8.93(d,J＝53.4Hz,1H),8.77(d,J＝8.6Hz,1H),8.39(s,1H),8.31(d,J＝8.8Hz,1H),8.19–8.11(m,3H),7.92(d,J＝8.5Hz,1H),7.65(d,J＝8.5Hz,1H),5.12–4.81(m,2H),4.35(m,J＝15.4Hz,2H),4.02(s,3H),3.78–3.55(m,5H),3.23(t,J＝12.1Hz,2H),2.32–1.94(m,3H).
example 2: 1- (1- (1H-1,2, 4-triazole-3-carbonyl) piperidin-3-yl) -3-methyl-8- (6- (1-methyl- 1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
20mg (0.0455mmol) of compound 111, 6.2mg (0.0546mmol) of 1H-1,2, 4-triazole-3-carboxylic acid, 9.23mg (0.0683mmol) of HOBt and 13.09mg of EDCI are suspended in 2ml of dichloromethane, 13.9mg (0.137mmol) of triethylamine are added and stirred at room temperature for 4 hours, TLC (DCM: MeOH ═ 10:1) shows that most of the starting materials have not reacted, 9.3mg of 1H-1,2, 4-triazole-3-carboxylic acid, 26mg of HATU and 15mg of triethylamine are added and stirred at room temperature overnight, TLC (DCM: MeOH ═ 10:1) shows that most of the starting materials have reacted, 10ml of saturated sodium bicarbonate solution is added and stirred for 1 hour, the organic phase is separated, the aqueous phase is extracted with 2 × 5ml of dichloromethane, the organic phases are combined, dried and evaporated to dryness, the preparative purification (dichloromethane: MeOH ═ 10:1) gives the target compound of example 2, 17.8mg of the powder, yield is 73mg of MS + 535M [ LC ++]+,tR＝1.463min.1H NMR(400MHz,DMSO+D2O)9.41(d,J＝7.9Hz,1H),9.14(d,J＝6.0Hz,1H),9.00–8.91(m,1H),8.87–8.79(m,1H),8.78–8.65(m,2H),8.64–8.44(m,2H),8.39(s,1H),8.22–7.96(m,1H),5.56–4.07(m,3H),4.00(d,J＝16.3Hz,3H),3.60(d,J＝13.2Hz,3H),3.44–3.17(m,2H),3.00–2.82(m,1H),2.31–2.14(m,1H).
Example 3: 3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) piper ine Pyridin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
20mg (0.0455mmol) of compound 111 was dissolved in 2ml of dichloromethane, 6.9mg of triethylamine (0.0683mmol) and 6.35mg (0.0546mmol) of methanesulfonyl chloride were added and stirred at room temperature overnight, TLC (DCM: MeOH ═ 10:1) showed completion of the reaction, 5ml of saturated sodium bicarbonate solution was added and stirred for 20 minutes, the organic phase was separated, the aqueous phase was extracted with 2 × 5ml of dichloromethane, the organic phases were combined, dried and evaporated to dryness to prepare TLC purification (dichloromethane: MeOH ═ 10:1) to give the title compound of example 3 as a 10mg of pale yellow powder in 42.5% yield LC-MS:518[ M +1 ═ 10: 1]]+,tR＝1.551min.1HNMR(400MHz,CDCl3)8.95(d,J＝2.0Hz,1H),8.76(s,1H),8.44–8.00(m,5H),7.95(d,J＝8.9Hz,1H),7.69(d,J＝7.8Hz,1H),5.15–5.03(m,1H),4.21(d,J＝8.9Hz,1H),4.02(s,3H),4.00–3.80(m,2H),3.62(s,3H),3.02–2.75(m,5H),2.34–1.83(m,3H).
Example 4: 1- (1- ((S) -2-hydroxypropionyl) piperidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyri-dine) Oxazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
80mg (0.156mmol) of the hydrochloride of compound 111, 21.1mg (0.234mmol) of L-lactic acid, 31.6mg (0.234mmol) of HOBt and 44.9mg of EDCI (E: (D) (D))0.234mmol) was suspended in 5ml dichloromethane, 0.153M1(1.1mmol) triethylamine was added with stirring and stirred at room temperature overnight, TLC (DCM: MeOH ═ 10:1) showed the completion of the reaction of the starting material, 15ml saturated sodium bicarbonate solution was added and stirred for 0.5h, the organic phase was separated, the aqueous phase was extracted with 2 × 15ml dichloromethane, the organic phases were combined, dried, filtered and evaporated to dryness, preparative TLC purification (dichloromethane: methanol ═ 10:1) gave the title compound of example 4, 45mg pale yellow powder, this product was dissolved in 75% ethanol, adjusted to pH 1 with 1M HCl, stirred for 0.5h and evaporated to dryness to give the hydrochloride salt LC-MS:512[ M + 1:1 ═ M +1]+,tR＝1.472min.1H NMR(400MHz,DMSO+D2O)9.27–9.19(m,1H),9.16–8.98(m,1H),8.70–8.32(m,5H),8.19(d,J＝11.1Hz,1H),8.00(dd,J＝15.9,8.4Hz,1H),5.63–4.31(m,3H),4.24–4.05(m,2H),3.96(s,3H),3.77–3.70(m,1H),3.58(s,3H),3.47–3.22(m,1H),2.97–2.64(m,1H),2.43–1.89(m,2H),1.33–1.26(m,3H).
Example 5: 1- (1- ((R) -2-Hydroxypropionyl) piperidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyranyl) Oxazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
80mg (0.156mmol) of the hydrochloride of compound 111, 21.1mg (0.234mmol) of L-lactic acid, 31.6mg (0.234mmol) of HOBt and 44.9mg of EDCI (0.234mmol) are suspended in 5ml of dichloromethane, 0.153M1(1.1mmol) of triethylamine is added with stirring, the mixture is stirred at room temperature overnight, TLC (DCM: MeOH 10:1) shows the completion of the reaction of the starting materials, 15ml of saturated sodium bicarbonate solution is added and stirred for 0.5h, the organic phase is separated off, the aqueous phase is extracted with 2 × 10ml of dichloromethane, the organic phases are combined, dried, filtered and evaporated to dryness, and the preparative TLC purification (dichloromethane: MeOH 10:1) gives the target compound of example 5, 45mg of light yellow powder LC-MS:512[ M + 1] M +1]+,tR＝1.476min.1H NMR(400MHz,CDCl3)9.09–8.63(m,2H),8.43–8.18(m,2H),8.11–7.83(m,4H),7.67–7.49(m,1H),5.10–4.48(m,3H),3.99(d,J＝2.1Hz,3H),3.59(s,3H),3.34–1.51(m,6H),1.47–1.14(m,4H).
(II) route II:
intermediate 140: 3- ((6-bromo-3-nitroquinolin-4-yl) amino) pyrrolidine-1-carboxylic acid tert-butyl ester
10g (34.3mmol) of Compound 3 and 11.3g (63.36mmol) of Compound 140A were dissolved in 100mL of dichloromethane, and 8.76mL (62.8mmol) of triethylamine was added thereto, followed by stirring at room temperature overnight. And (5) detecting by TLC, and after the reaction is finished, spin-drying the solvent to obtain a crude product. The crude product was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate 1/1, V/V) to obtain 13g of product as a yellow powder in 85% yield. LC-MS 437,439[ M + 1]]+,tR＝2.489min.
Intermediate 141: 3- ((3-amino-6-bromoquinolin-4-yl) amino) pyrrolidine-1-carboxylic acid tert-butyl ester
13g (29.7mmol) of intermediate 140 were dissolved in 100mL of N, N-dimethylformamide under an ice-water bath. 33.5g (148.5mmol) of stannous dichloride dihydrate are added in portions over 30 minutes and stirred at room temperature for 2 hours. TLC detection, after the reaction is finished, 10% sodium hydroxide aqueous solution is added into the reaction solution dropwise until the pH value is 8-9, the filtration is carried out, the filtrate is extracted by dichloromethane, the filter cake is washed by dichloromethane, the organic phases are combined, washed by water and brine, dried and dried in a spinning mode to obtain 11.9g of a product, a dark yellow oily substance, and the yield is 99%. LC-MS 407,409[ M + 1]]+,tR＝1.710min.
An intermediate 142: 3- (8-bromo-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester
Under an ice-water bath, 1.3g (3.19mmol) of intermediate 141 was dissolved in 10mL of dichloromethane, and 1.47mL (10.53mmol) of triethylamine was added thereto and stirred for 5 minutes. A solution of 0.47g (1.6mmol) of triphosgene in 10mL of dichloromethane was added dropwise and stirred at 0 ℃ for 4 hours. And (3) TLC detection, after the reaction is finished, 25mL of saturated sodium bicarbonate solution is added into the reaction solution dropwise for quenching, the stirring is carried out for 10 minutes, an organic phase is separated, a water phase is extracted by dichloromethane, and the organic phase is combined, dried and spin-dried to obtain a crude product. The crude product was subjected to silica gel column chromatography (eluent: dichloromethane/methanol-10/1, V/V) to obtain 0.7g of the product as a yellow powder with a yield of 50.7%. LC-MS 433,435[ M + 1]]+,tR＝1.973min.
Intermediate 143: 3- (8-bromo-3-methyl-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester
5g (11.3mmol) of intermediate 142 was dissolved in 100mL of dichloromethane, 0.42g (1.13mmol) of tetrabutylammonium bromide and 100mL of a 10% aqueous solution of sodium hydroxide were added, and the mixture was stirred for 10 minutes, 2.1mL (33.8mmol) of methyl iodide was added, and the mixture was stirred for 4 hours. And (3) TLC detection, standing for layering after the reaction is finished, separating out an organic phase, extracting an aqueous phase by using dichloromethane, combining the organic phases, drying and spin-drying to obtain 4.9g of a product, namely a yellow solid with the yield of 95%. LC-MS 447,449[ M + 1]]+,tR＝2.170min.
Intermediate 144: 3- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) piperidin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester
Under nitrogen, 1.2g (2.68mmol) of intermediate 143 and 1.44g (5.04mmol) of intermediate 9A were dissolved in 40mL of dioxane, 5.16g (15.8mmol) of cesium carbonate, 10.5mL of 2M aqueous sodium carbonate solution and 0.22g (0.268mmol) of [1, 1-bis (diphenylphosphino) ferrocene]Palladium chloride was heated at 110 ℃ for 5 hours. And (3) TLC detection, after the reaction is finished, most of dioxane is rotated out, water is added, dichloromethane is used for extraction, organic phases are combined, and the mixture is dried and rotated to obtain a crude product. The crude product was subjected to silica gel column chromatography (dichloromethane/methanol-20/1, V: V) to obtain 1.3g of the product as a reddish earth solid in 92.8% yield. LC-MS 526[ M + 1]]+,tR＝1.812min.
Intermediate 145: 3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one hydrochloride
1.3g of intermediate 144 was dissolved in 30mL of dichloromethane in an ice-water bath, and hydrogen chloride gas was introduced into the reaction solution for thirty minutes. TLC detection, after the reaction is finished, filtration is carried out, the solid is washed by dichloromethane and is dried by suction under reduced pressure, and 1.3g of crude product of the solid hydrochloride in the crude yield is obtained>100％。LC-MS:426[M+1]+,tR＝1.274min.
Example 6: 3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) pyridine Pyrrolidin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
100mg (0.194mmol) of intermediate 145 was dissolved in 5mL of dichloromethane, 29.4mg (0.291mmol) of triethylamine was added, and 26.7mg (0.233mmol) of methanesulfonyl chloride was further added, and the mixture was stirred at room temperature overnight. And (3) TLC detection, after the reaction is finished, adding 10mL of saturated sodium bicarbonate aqueous solution, stirring for 20 minutes, demixing, extracting the aqueous phase by using dichloromethane, combining the organic phases, drying and spin-drying to obtain a crude product. The crude product was purified on a preparative silica gel pad (dichloromethane/methanol-10/1, V/V) to afford 53mg of the title compound of example 6 as a white solid in 44.9% yield. LC-MS 504[ M + 1]]+,tR＝1.499min.1H NMR(400MHz,CDCl3)8.91(s,1H),8.78(s,1H),8.34(s,1H),8.29(d,J＝8.9Hz,1H),8.10(s,1H),8.04(s,2H),7.93(d,J＝8.6Hz,1H),7.65(d,J＝8.0Hz,1H),5.87–5.72(m,1H),4.11–4.02(m,1H),4.00(s,3H),3.97–3.92(m,1H),3.86–3.81(m,1H),3.63(s,3H),3.61–3.57(m,1H),2.97(s,3H),2.91–2.82(m,1H),2.58–2.44(m,1H).
Example 7: 1- (1- (2-hydroxyacetyl) pyrrolidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazole-) 4-yl) pyridin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
100mg (0.194mmol) of intermediate 145, 69mg (0.36mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 48.6mg (0.36mmol) of 1-hydroxybenzotriazole and 21.9mg (0.288mmol) of glycolic acid are dissolved in 5mL of dichloromethane, and 72.8mg (0.72mmol) of triethylamine are added and stirred at room temperature overnight. And (3) TLC detection, after the reaction is finished, adding 10mL of saturated sodium bicarbonate aqueous solution, stirring for 20 minutes, demixing, extracting the aqueous phase by using dichloromethane, combining the organic phases, drying and spin-drying to obtain a crude product. The crude product was purified by preparative silica gel plate (dichloromethane/methanol-10/1, V/V) to obtain 30mg of the title compound of example 7 as a pale yellow solid in 26.1% yield. LC-MS 484[ M + 1]]+,tR＝1.33min.1H NMR(400MHz,CDCl3)8.88–8.79(m,2H),8.31(d,J＝8.9Hz,1H),8.23–7.96(m,3H),7.94–7.86(m,2H),7.66–7.60(m,1H),5.86–5.62(m,1H),4.43–4.06(m,3H),4.00(s,3H),3.97–3.89(m,1H),3.83–3.73(m,1H),3.63(d,J＝8.9Hz,2H),3.61–3.51(m,1H),3.22–3.05(m,3H),2.89–2.80(m,1H),2.61–2.43(m,1H).
Example 8: 1- (1- (1H-1,2, 4-triazole-3-carbonyl) pyrrolidine-3-yl) -3-methyl-8- (6- (1-methyl) Yl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
In an ice-water bath, 48.8mg (0.43mmol) of 1,2, 4-triazole-3-carboxylic acid and 200.76mg (0.528mmol) of 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate were dissolved in 5mL of dichloromethane, 97mg (0.96mmol) of triethylamine was added thereto, and after stirring at 0 ℃ for 30 minutes, 100mg (0.24mmol) of intermediate 145 was further added thereto, and the mixture was stirred at room temperature overnight. And (3) TLC detection, after the reaction is finished, adding 10mL of saturated sodium bicarbonate aqueous solution, stirring for 20 minutes, demixing, extracting the aqueous phase by using dichloromethane, combining the organic phases, drying and spin-drying to obtain a crude product. The crude product was purified on a preparative silica gel pad (dichloromethane/methanol-10/1, V/V) to afford 40mg of the title compound of example 8 as a white solid in 32% yield. The product was dissolved in 75% ethanol, adjusted to pH 1 with 1M HCl, stirred for 0.5h, and evaporated to dryness to obtain the hydrochloride. LC-MS 521[ M + 1]]+,tR＝1.337min.1H NMR(400MHz,DMSO+D2O)9.33(d,J＝6.6Hz,1H),9.11(d,J＝3.2Hz,1H),8.87–8.71(m,2H),8.68–8.58(m,2H),8.55–8.37(m,3H),8.30(d,J＝8.9Hz,1H),8.11(dd,J＝23.7,8.5Hz,1H),6.14–6.02(s,1H),4.84–4.10(m,3H),3.97(s,3H),3.57(d,J＝11.5Hz,3H),3.50–3.23(m,1H),2.96–2.61(m,2H).
Example 9: 3-Methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1-methylpyrrolidine- 3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
20mg (0.5mmol) of 60% sodium hydride was suspended in 5mL of tetrahydrofuran in an ice-water bath, and after stirring for 5 minutes, 50mg (0.1mmol) of intermediate 145 was added, and after stirring for 10 minutes, 7. mu.L (0.1mmol) of iodomethane was added dropwise and the mixture was stirred at room temperature for 2 hours. And (3) detecting by TLC, after the reaction is finished, dropwise adding 10mL of water, extracting by using dichloromethane, extracting the water phase by using dichloromethane, combining organic phases, drying and spin-drying to obtain a crude product. The crude product was purified on a preparative silica gel pad (dichloromethane/methanol-10/1, V/V) to obtain 35mg of the title compound of example 9 as a white solid in 79.1% yield. LC-MS 440[ M + 1]]+,tR＝1.250min.1H NMR(400MHz,CDCl3+MeOD)9.52–9.04(m,3H),8.92–8.68(m,2H),8.51–8.48(m,1H),8.31–8.21(m,3H),4.29–3.95(m,3H),3.71(s,4H),3.14(s,3H),3.00–2.82(m,1H),2.64–1.57(m,2H).
Example 10: 1- (1-ethylpyrrolidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridine- 3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
40mg (1mmol) of 60% sodium hydride was suspended in 5mL of tetrahydrofuran in an ice-water bath, and after stirring for 5 minutes, 100mg (0.2mmol) of intermediate 145 was added, and after stirring for 10 minutes, 31.2mg (0.2mmol) of iodoethane was added dropwise, and the mixture was stirred at room temperature for 2 hours. And (3) detecting by TLC, after the reaction is finished, dropwise adding 10mL of water, extracting by using dichloromethane, extracting the water phase by using dichloromethane, combining organic phases, drying and spin-drying to obtain a crude product. The crude product was purified on preparative silica gel plates (dichloromethane/methanol-10/1, V)V) 20mg of the title compound of example 10 was obtained as a white solid in 22.1% yield. The product was dissolved in 75% ethanol, adjusted to pH 1 with 1M HCl, stirred for 0.5h, and evaporated to dryness to obtain the hydrochloride. LC-MS 454[ M + 1]]+,tR＝1.305min.1H NMR(400MHz,DMSO+D2O)9.34(d,J＝7.2Hz,1H),9.23–9.12(m,1H),8.84–8.71(m,2H),8.59(s,1H),8.42(q,J＝9.2Hz,2H),8.28(s,1H),8.12(dd,J＝8.4,3.5Hz,1H),6.36–6.13(m,1H),4.45–4.13(m,1H),3.96(s,4H),3.79–3.68(m,1H),3.61(d,J＝8.6Hz,3H),3.57–3.13(m,3H),3.04–2.65(m,2H),1.42–1.29(m,3H).
Example 11: 1- (1-acetylpyrrolidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyri-dine Pyridin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
50mg (0.1mmol) of intermediate 145 was suspended in 5mL of dichloromethane, 50mg (0.5mmol) of triethylamine was added dropwise thereto, and after stirring for 5 minutes, 15mg (0.15mmol) of acetic anhydride was added thereto, and the mixture was stirred at room temperature for 2 hours. And (5) detecting by TLC, and after the reaction is finished, spin-drying the reaction solution to obtain a crude product. The crude product was purified on preparative silica gel plate (dichloromethane/methanol-10/1, V/V) to afford 43mg of the title compound of example 11 as a white yellow solid in 92.1% yield. The product was dissolved in 75% ethanol, adjusted to pH 1 with 1M HCl, stirred for 0.5h, and evaporated to dryness to obtain the hydrochloride. LC-MS 468[ M + 1]]+,tR＝1.407min.1H NMR(400MHz,DMSO)9.39(d,J＝4.4Hz,1H),9.17(d,J＝14.9Hz,1H),8.94–8.69(m,3H),8.60–8.40(m,3H),8.31(dd,J＝8.6,4.4Hz,1H),6.16–5.83(m,1H),4.33–4.05(m,2H),3.99(s,3H),3.79–3.49(m,2H),3.61(s,3H),2.88–2.58(m,2H),2.02(d,J＝15.3Hz,1H).
Example 12: 1- (1-benzylpyrrolidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridine- 3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
20mg (0.5mmol) of 60% sodium hydride was suspended in 5mL of tetrahydrofuran in an ice-water bath, and after stirring for 5 minutes, 50mg (0.1mmol) of intermediate 145 was added, and after stirring for 10 minutes, 17.14mg (0.1mmol) of benzyl bromide was added dropwise, and the mixture was stirred at room temperature for 2 hours. And (3) detecting by TLC, after the reaction is finished, dropwise adding 10mL of water, extracting by using dichloromethane, extracting the water phase by using dichloromethane, combining organic phases, drying and spin-drying to obtain a crude product. The crude product was purified on a preparative silica gel pad (dichloromethane/methanol-10/1, V/V) to afford 18mg of the title compound of example 12 as a white solid in 35.3% yield. LC-MS 516[ M + 1]]+,tR＝1.486min.1H NMR(400MHz,DMSO+D2O)9.39(s,1H),9.19(d,J＝26.9Hz,1H),8.92–8.70(m,2H),8.68–8.57(m,1H),8.48(d,J＝9.0Hz,1H),8.42(d,J＝9.0Hz,1H),8.38–8.26(m,1H),8.13(dd,J＝17.1,8.3Hz,1H),7.76–7.22(m,5H),6.42–6.16(m,1H),4.82–4.32(m,2H),4.10–3.87(m,6H),3.64–3.37(m,4H),3.11–2.67(m,2H).
Example 13: 1- (1- ((4-chlorophenyl) sulfonyl) pyrrolidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-) Pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
100mg (0.2mmol) of intermediate 145 was suspended in 5mL of dichloromethane, 100mg (1mmol) of triethylamine was added dropwise thereto, and after stirring for 5 minutes, 63.3mg (0.3mmol) of 4-chlorobenzenesulfonyl chloride was added thereto, and the mixture was stirred at room temperature overnight. And (3) TLC detection, after the reaction is finished, adding 10mL of saturated sodium bicarbonate aqueous solution, stirring for 20 minutes, demixing, extracting the aqueous phase by using dichloromethane, combining the organic phases, drying and spin-drying to obtain a crude product. Subjecting the crude product to silica gel column chromatography (dichloromethane)V/methanol 20/1, V) to yield 50mg of the title compound of example 13 as a white solid in 41.7% yield. LC-MS 600[ M + 1]]+,tR＝1.860min.1H NMR(400MHz,CDCl3)8.92(d,J＝2.0Hz,1H),8.77(s,1H),8.41–8.17(m,4H),8.07(s,1H),7.95(dd,J＝8.8,1.6Hz,1H),7.79(d,J＝8.5Hz,3H),7.54(d,J＝8.5Hz,2H),5.73–5.50(m,1H),4.00(s,3H),3.97–3.80(m,2H),3.71(t,J＝10.3Hz,1H),3.59(s,3H),3.34–3.22(m,1H),2.97–2.69(m,1H),2.45–2.25(m,1H).
Example 14: 3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1-p-toluenesulfonyl) Pyrrolidin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
50mg (0.1mmol) of intermediate 145 was suspended in 5mL of dichloromethane, 50mg (0.5mmol) of triethylamine was added dropwise thereto, and after stirring for 5 minutes, 30mg (0.15mmol) of p-toluenesulfonyl chloride was added and the mixture was stirred at room temperature for 2 hours. And (3) TLC detection, after the reaction is finished, adding 10mL of saturated sodium bicarbonate aqueous solution, stirring for 20 minutes, demixing, extracting the aqueous phase by using dichloromethane, combining the organic phases, drying and spin-drying to obtain a crude product. The crude product was purified on preparative silica gel plate (dichloromethane/methanol-10/1, V/V) to afford 40mg of the title compound of example 14 as a white solid in 69.1% yield. LC-MS 580[ M + 1]]+,tR＝1.792min.1H NMR(400MHz,CDCl3)8.94(d,J＝2.1Hz,1H),8.76(s,1H),8.49(br s,2H),8.30(d,J＝8.8Hz,1H),8.22(br s,1H),8.08(s,1H),7.97(dd,J＝8.9,1.6Hz,1H),7.81(d,J＝7.8Hz,1H),7.75(d,J＝8.2Hz,2H),7.38(d,J＝8.0Hz,2H),5.69–5.43(m,1H),4.00(s,3H),3.96–3.81(m,2H),3.67(t,J＝10.7Hz,1H),3.60(s,3H),3.20(q,J＝6.3Hz,1H),2.86–2.68(m,1H),2.48(s,3H),2.34–2.19(m,1H).
Example 15: 3- (3-methyl)-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-di hydro-1H-imidazo [4,5-c ]]Quinolin-1-yl) pyrrolidine-1-sulfonamides
100mg (0.2mmol) of intermediate 145 was suspended in 10mL of dioxane, 100mg (1mmol) of triethylamine was added dropwise, 57.6mg (0.6mmol) of sulfamide was added thereto, and the mixture was refluxed for 8 hours. And (3) TLC detection, after the reaction is finished, spin-drying the reaction solution, adding water, extracting with dichloromethane, combining organic phases, drying, and spin-drying to obtain a crude product. The crude product was purified by preparative silica gel plate (dichloromethane/methanol-10/1, V/V) to obtain 18mg of the title compound of example 15 as a solid in the form of a brown solid with a yield of 17.8%. LC-MS 505[ M + 1]]+,tR＝1.409min.1H NMR(400MHz,CDCl3+MeOD)8.96(d,J＝2.1Hz,1H),8.85(s,1H),8.68(s,1H),8.40(d,J＝6.8Hz,1H),8.31(d,J＝8.9Hz,1H),8.19(s,1H),8.12–7.99(m,2H),7.81(d,J＝8.3Hz,1H),5.92–5.84(m,1H),4.01(s,3H),3.97–3.79(m,3H),3.69(s,3H),3.52–3.43(m,1H),2.88–2.69(m,1H),2.51–2.43(m,1H).
Example 16: 3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (2,2, 2-trifluoro-l) Acetyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
100mg (0.194mmol) of intermediate 145 (which contains a portion of the trifluoroacetate salt), 69mg (0.36mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 48.6mg (0.36mmol) of 1-hydroxybenzotriazole and 40.7mg (0.36mmol) of 1,2, 4-triazole-3-carboxylic acid are dissolved in 5mL of dichloromethane, and 72.8mg (0.72mmol) of triethylamine are added and stirred at room temperature overnight. TLC detection, after the reaction is finished, 10mL of saturated carbonic acid is addedAqueous sodium hydrogen solution, stirring for 20 minutes, demixing, extracting the aqueous phase with dichloromethane, combining the organic phases, drying and spin-drying to obtain a crude product. The crude product was purified by preparative silica gel plate (dichloromethane/methanol-10/1, V/V) to obtain 30mg of the target compound of example 16 as a pale yellow solid in 26.1% yield. LC-MS 522[ M + 1]]+,tR＝1.690min.1H NMR(400MHz,CDCl3)8.86(s,1H),8.78(s,1H),8.30(d,J＝9.1Hz,1H),8.16(d,J＝11.8Hz,1H),8.02(s,2H),7.89(dd,J＝16.4,7.4Hz,2H),7.60(d,J＝8.1Hz,1H),5.91–5.62(m,1H),4.74–4.37(m,1H),4.31–4.06(m,2H),4.00(s,3H),3.97–3.78(m,1H),3.62(s,3H),3.15–2.89(m,1H),2.70–2.37(m,1H).
(III) route III:
intermediate 200: (1r,4r) -4- ((6-bromo-3-nitroquinolin-4-yl) amino) cyclohexanol
1g (3.49mmol) of intermediate 3 and 0.723g (6.28mmol) of trans 4-aminocyclohexanol were dissolved in 10mL of dichloromethane, 0.876mL (6.28mmol) of triethylamine was added, and the mixture was stirred overnight. TLC detection, after the reaction is finished, filtration is carried out, a filter cake is washed by dichloromethane and dried in vacuum, and 1.9g of crude product, yellow solid and crude yield are obtained>100％。LC-MS:366,368[M+1]+,tR＝1.902min.
An intermediate 201: (1r,4r) -4- ((3-amino-6-bromoquinolin-4-yl) amino) cyclohexanol
1.9g (3.49mmol) of intermediate 200 are dissolved in 20mL of ethanol and 3 are added in portions9g (17.45mmol) of stannous chloride were stirred at room temperature for 2 hours. TLC detection, after the reaction is finished, ethanol is dried in a spinning mode, saturated sodium bicarbonate is added, a water layer is extracted by ethyl acetate, organic phases are combined, and the organic phases are dried and dried in a spinning mode. 1.2g of crude product are obtained as a yellow solid in crude yield>100％。LC-MS:336,338[M+1]+,tR＝1.351min.
Intermediate 202: 8-bromo-1- ((1r,4r) -4-hydroxycyclohexyl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1.2g (3.49mmol) of intermediate 201 was suspended in 20mL of dichloromethane at 0 ℃, 1.7mL (12.22mmol) of triethylamine was added, and a solution of 0.52g (1.75mmol) of triphosgene in 20mL of dichloromethane was added dropwise and stirred for 5 hours. TLC detection, after the reaction is finished, adding saturated sodium bicarbonate solution, stirring for 30 minutes, demixing, extracting the water phase with dichloromethane, combining the organic phases, drying and spin-drying. 1g of crude product was obtained, which was extremely polar and was used in the next reaction without purification.
Intermediate 203: 8-bromo-1- ((1r,4r) -4-hydroxycyclohexyl) -3-methyl-1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1g (3.49mmol) of intermediate 202 was suspended in 30mL of dichloromethane, 0.11g (0.349mmol) of tetrabutylammonium bromide and 30mL of 10% sodium hydroxide solution were added, and after stirring for 10 minutes, 1.5g (10.47mmol) of methyl iodide was added, and the mixture was stirred at room temperature for 7 hours. And (3) TLC detection, standing for layering after the reaction is finished, separating an organic phase, extracting a water phase by using dichloromethane, combining the organic phases, drying, and spin-drying to obtain a crude product. The crude product was subjected to silica gel column chromatography (eluent: ethyl acetate/methanol 20/1, V: V) to give 0.4g of product as a dark yellow solid in 38.8% yield. LC-MS 376,378[ M + 1]]+,tR＝1.541min.
Example 17: 1- ((1r,4r) -4-hydroxycyclohexyl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridine Pyridin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
0.1g (0.36mmol) of intermediate 203 and 0.15g (0.54mmol) of intermediate 9A are dissolved in 15mL of dioxane under nitrogen protection, 0.469g (1.44mmol) of cesium carbonate, 15mL of 2M aqueous sodium carbonate solution are added, and 0.029g (0.036mmol) of [1, 1-bis (diphenylphosphino) ferrocene are added]Palladium chloride was heated at 110 ℃ for 5 hours. And (3) TLC detection, after the reaction is finished, most of dioxane is rotated out, water is added, dichloromethane is used for extraction, organic phases are combined, and the mixture is dried and rotated to obtain a crude product. The crude product was purified on preparative silica gel plates (dichloromethane/methanol-10/1, V/V) to yield 0.032g of the title compound of example 17 as a beige powder. The product was dissolved in 75% ethanol, adjusted to pH 1 with 1M HCl, stirred for 0.5h, and evaporated to dryness to obtain the hydrochloride. LC-MS:455[ M +1]+,tR＝1.420min.1H NMR(400MHz,DMSO+D2O)9.24(s,1H),9.07(s,1H),8.59(s,1H),8.49(d,J＝9.6Hz,2H),8.40(s,2H),8.22(s,1H),8.06(d,J＝8.4Hz,1H),5.03(t,J＝11.8Hz,1H),3.95(s,3H),3.66–3.59(m,1H),3.56(s,3H),2.39–2.16(m,1H),2.07(t,J＝12.5Hz,4H),1.62–1.41(m,3H).
(IV) route IV:
intermediate 205: (1s,4s) -4- ((6-bromo-3-nitro-4-yl) amino) cyclohexanol
Cis-4-aminocyclohexanol (1.06g,6.98mmol) was dissolved in 10ml of dichloromethane, 1g (3.49mmol) of Compound 3 and 1.94ml (13.96mmol) of triethylamine were added, stirred at room temperature for 3 days, filtered, rinsed with a small amount of dichloromethane, and dried by suction to give crude yellow solid, crude 1.945g, crude yield>100％。LC-MS:366,368[M+1]+,tR＝1.913min.。
Intermediate 206: (1s,4s) -4- ((3-amino-6-bromoquinolin-4-yl) amino) cyclohexanol
Intermediate 205(1.945g, 3.49mmol) was dissolved in 20ml ethanol and 3.937g (17.45mmol) of water and stannous chloride were added in portions and stirred at room temperature overnight. Evaporating ethanol, adding 50ml ethyl acetate, adjusting pH to 9 with 10% sodium hydroxide solution, separating, extracting water phase with ethyl acetate, mixing organic phases, drying, evaporating to obtain 1.2g yellow solid crude product with crude yield>100％。LC-MS:336,338[M+1]+,tR＝1.447min.。
Intermediate 207: 8-bromo-1- ((1s,4s) -4-hydroxycyclohexyl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
Intermediate 206(1.2g, 3.49mmol) was dissolved in 20ml dichloromethane, 1.7ml (12.22mmol) triethylamine was added, cooled to 0 ℃ and a solution of 0.52g (1.75mmol) triphosgene in 20ml dichloromethane was added dropwise, and the reaction was maintained at 0 ℃ for 4 h. Adding 50ml of saturated sodium bicarbonate solution, stirring for 20min, separating, extracting the water phase with dichloromethane, combining the organic phases, drying, evaporating to obtain a crude product, and performing silica gel column chromatography on the crude product (eluent: ethyl acetate: methanol ═ 1:20) to obtain 0.2g of white solid with the yield of 15.82%. LC-MS 362,364[ M + 1]]+,tR＝1.482min.
Intermediate 208: 8-bromo-1- ((1s,4s) -4-hydroxycyclohexyl) -3-methyl-1H-imidazo [4,5-c ] quinolin-2 (3H) -one
Dissolving the intermediate 207(200mg, 0.55mmol) in 10ml dichloromethane, adding 18mg (0.055mmol) tetrabutylammonium bromide and 10ml 10% sodium hydroxide solution, stirring for 5min, adding 234mg (1.65mmol) iodomethane, stirring at room temperature for 7.5h, standing, separating, extracting the aqueous phase with dichloromethane, combining the organic phases, drying, evaporating to dryness to obtain a crude product, and performing silica gel column chromatography on the crude product (methanol: dichloromethane ═ 1:10) to obtain 120mg white solid with the yield of 57.97%.
Example 18: 1- ((1s,4s) -4-hydroxycyclohexyl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridine Pyridin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
Intermediate 208(120mg, 0.32mmol) was dissolved in 3ml dioxane, 137mg (0.48mmol) intermediate 9A, 417mg (1.28mmol) cesium carbonate, 2ml 2M aqueous sodium carbonate solution were added, and 12mg (0.016mmol) of [1, 1-bis (diphenylphosphino) ferrocene ] was added under nitrogen protection]Palladium chloride was heated at 110 ℃ for 8 hours. Cooling to room temperature, evaporating dioxane to dryness, adding 10ml of water and 10ml of dichloromethane, separating, extracting the water phase with dichloromethane, combining the organic phases, drying, evaporating to dryness to obtain a crude product, and performing silica gel column chromatography on the crude product (methanol: dichloromethane ═ 1:10) to obtain the target compound of example 18, 125mg of orange-yellow solid, and the yield is 85.94%. LC-MS:455[ M +1]+,tR＝1.600min.1H NMR(400MHz,DMSO)8.99(s,1H),8.89(s,1H),8.78–8.20(m,3H),8.15(d,J＝8.8Hz,1H),8.07(s,1H),8.00(d,J＝8.7Hz,1H),7.77(d,J＝8.0Hz,1H),4.95–4.76(m,1H),4.65(br s,1H),3.98(s,1H),3.92(s,3H),3.52(s,3H),2.81(s,2H),1.91(d, J ═ 9.2Hz,2H),1.69(t, J ═ 11.3Hz,4H), this product was dissolved in 75% ethanol, adjusted to pH 1 with 1M HCl, stirred for 0.5H, and evaporated to dryness to give the hydrochloride salt.
Example 19: 1- ((1s,4s) -4-hydroxycyclohexyl) -3-methyl-8- (6-phenylpyridin-3-yl) -1H-imidazole And [4,5-c ]]Quinolin-2 (3H) -ones
74.7mg (0.32mmol) of 5-bromo-2-phenylpyridine, 97.5mg (0.384mmol) of pinacol diboron, 94.2mg (0.96mmol) of potassium acetate and 10.6mg (0.013mmol) of Pd (dppf) Cl are added under nitrogen2.CH2Cl2Suspending the mixture in 3ml of 1, 4-dioxane, heating to 95 ℃, stirring for 2h, and cooling the obtained reaction solution for later use. To the above reaction mixture were added intermediate 208(80mg, 0.213mmol), 278mg (0.852mmol) cesium carbonate, 1ml of 2M aqueous sodium carbonate solution, 3ml of 1, 4-dioxane, and 7mg (0.0085mmol) Pd (dppf) Cl under nitrogen protection2.CH2Cl2Stirring was carried out at 110 ℃ for 4.5 hours. Cooling to room temperature, evaporating dioxane to dryness, adding 10ml of water and 10ml of dichloromethane, separating, extracting the water phase with dichloromethane, combining the organic phases, drying, evaporating to dryness to obtain a crude product, and performing silica gel column chromatography on the crude product (methanol: dichloromethane ═ 1:10) to obtain the target compound of example 19, 20mg of pale yellow powder and the yield of 21%. LC-MS:451[ M + 1]]+,tR＝1.913min.1H NMR(400MHz,DMSO)9.19(s,1H),8.94(s,1H),8.45(s,1H),8.20(dd,J＝8.0,4.8Hz,4H),8.10(dd,J＝17.4,8.4Hz,2H),7.60–7.45(m,3H),4.89(t,J＝12.7Hz,1H),4.72(s,1H),4.00(s,1H),3.55(s,3H),2.84(s,2H),1.92(d,J＝12.1Hz,2H),1.71(t,J＝11.3Hz,4H).
Example 20: 1- ((1s,4s) -4-hydroxycyclohexyl) -8- (6-methoxy-5-methylpyridin-3-yl) -3-methyl radical-1H-imidazo [4 ],5-c]Quinolin-2 (3H) -ones
0.1g (0.27mmol) of intermediate 208 and 0.134g (0.54mmol) of 6-methoxy-5-methylpyridine-3-boronic acid pinacol ester (intermediate 4a) are dissolved in 15mL of dioxane under nitrogen protection, 0.351g (1.08mmol) of cesium carbonate, 15mL of 2M aqueous sodium carbonate solution are added, and 0.022g (0.027mmol) of [1, 1-bis (di-phenylphosphino) ferrocene are added]Palladium chloride was heated at 110 ℃ for 5 hours. And (3) TLC detection, after the reaction is finished, most of dioxane is rotated out, water is added, dichloromethane is used for extraction, organic phases are combined, and the mixture is dried and rotated to obtain a crude product. The crude product was purified on a preparative silica gel pad (dichloromethane/methanol-10/1, V/V) to obtain 50mg of the title compound of example 20 as a white solid in 44.6% yield. LC-MS 419[ M + 1]]+,tR＝1.759min.1HNMR(400MHz,DMSO)8.89(s,1H),8.51(s,2H),8.13(d,J＝8.8Hz,1H),8.08(s,1H),7.99–7.87(m,1H),4.84(t,J＝12.8Hz,1H),4.58(s,1H),3.97(s,3H),3.53(s,3H),2.80(s,2H),2.26(s,3H),1.92(d,J＝12.4Hz,2H),1.68(t,J＝11.4Hz,4H).
Example 21: 1- ((1s,4s) -4-hydroxycyclohexyl) -3-methyl-8- (1-phenyl-1H-pyrazol-4-yl) -1H- Imidazo [4, 5-c)]Quinolin-2 (3H) -ones
0.1g (0.27mmol) of intermediate 208 and 0.108g (0.4mmol) of 1-phenyl-1H-pyrazole-4-boronic acid pinacol ester (intermediate 4b) were dissolved in 15mL of dioxane under nitrogen protection, 0.351g (1.08mmol) of cesium carbonate, 15mL of 2M aqueous sodium carbonate solution and 0.022g (0.027mmol) of [1, 1-bis (di-phenylphosphino) ferrocene were added]Palladium chloride was heated at 110 ℃ for 5 hours. TLC detection, after the reaction is finished, most dioxane is rotated out, water is added, and methylene dichloride is usedAnd (4) performing alkane extraction, combining organic phases, drying and spin-drying to obtain a crude product. The crude product was purified on a preparative silica gel pad (dichloromethane/methanol-10/1, V/V) to afford 60mg of the title compound of example 21 as a pale yellowish white solid with a yield of 50.8%. LC-MS 440[ M + 1]]+,tR＝1.822min.1HNMR(400MHz,DMSO)9.22(s,1H),8.87(s,1H),8.61(s,2H),8.11(d,J＝8.7Hz,1H),8.06(d,J＝9.1Hz,1H),7.95(d,J＝8.3Hz,2H),7.57(t,J＝7.8Hz,2H),7.37(t,J＝7.2Hz,1H),4.93–4.79(m,1H),4.07(s,1H),3.94(s,1H),3.55(s,4H),2.93–2.68(m,2H),2.08–1.86(m,2H),1.85–1.50(m,4H).
Example 22: 1- ((1s,4s) -4-hydroxycyclohexyl) -3-methyl-8- (6-methylpyridin-3-yl) -1H-imidazole And [4,5-c ]]Quinolines-2(3H) -ketones
0.1g (0.27mmol) of intermediate 208 and 0.055g (0.4mmol) of 6-methylpyridine-3-boronic acid (intermediate 4c) were dissolved in 15mL of dioxane under nitrogen, 0.351g (1.08mmol) of cesium carbonate, 15mL of 2M aqueous sodium carbonate solution and 0.022g (0.027mmol) of [1, 1-bis (di-phenylphosphino) ferrocene were added]Palladium chloride was heated at 110 ℃ for 5 hours. And (3) TLC detection, after the reaction is finished, most of dioxane is rotated out, water is added, dichloromethane is used for extraction, organic phases are combined, and the mixture is dried and rotated to obtain a crude product. The crude product was purified by preparative silica gel plate (dichloromethane/methanol-10/1, V/V) to afford 68mg of the title compound of example 22 as a pale yellow solid in 65.38% yield. LC-MS 389[ M + 1]]+,tR＝1.29min.H NMR(400MHz,DMSO)8.92(d,J＝13.8Hz,2H),8.75–8.05(m,3H),7.96(d,J＝8.8Hz,1H),7.40(d,J＝8.0Hz,1H),4.83(t,J＝12.7Hz,1H),4.64(s,1H),3.97(s,1H),3.53(s,3H),3.23–3.08(m,1H),2.79(s,2H),2.55(s,3H),1.90(d,J＝12.9Hz,2H),1.80–1.47(m,5H).
(V) route five:
intermediate 218: 6-bromo-N- ((1r,4r) -4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) -3-nitroquinolin-4-amine
2.5g (7mmol) of intermediate 200 and 1.58g (10.5mmol) of tert-butyldimethylsilyl chloride were dissolved in 50mL of dichloromethane, 0.76g (11.2mmol) of imidazole was added, and the mixture was stirred at room temperature for 24 hours. TLC detection, after the reaction is finished, the reaction solution is dried by spinning, water and ethyl acetate are added for layering, the water layer is extracted by ethyl acetate, the organic phases are combined, dried and spun to obtain 3g of yellow solid.1HNMR(400MHz,CDCl3)9.53(d,J＝8.4Hz,1H),9.34(s,1H),8.32(d,J＝1.8Hz,1H),7.96–7.72(m,2H),4.18(dd,J＝8.7,3.8Hz,1H),4.01–3.66(m,1H),2.36–2.15(m,2H),1.98(dd,J＝9.9,3.8Hz,2H),1.70–1.47(m,4H),0.90(s,9H),0.07(d,J＝3.0Hz,6H).
Intermediate 219: 6-bromo-N- ((1r,4r) -4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) quinoline-3, 4-diamine
4.8g (10mmol) of intermediate 218 are suspended in 100mL of ethanol in an ice-water bath, and 11.28g (50mmol) of stannous dichloride dihydrate are added in portions over 30 minutes and stirred at room temperature for 2 hours. And (3) detecting by TLC, after the reaction is finished, dropwise adding a 10% sodium hydroxide aqueous solution into the reaction solution until the pH value is 8-9, filtering, extracting the filtrate by using dichloromethane, washing the filter cake by using dichloromethane, combining organic phases, washing by using water, washing by using brine, drying, and spin-drying to obtain 6g of a brownish red solid crude product which is directly used for the next reaction.
An intermediate 220: 8-bromo-1- ((1r,4r) -4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
Under an ice-water bath, 6g (10mmol) of intermediate 219 was dissolved in 80mL of dichloromethane, 3.5g (35mmol) of triethylamine was added, and the mixture was stirred for 5 minutes. A solution of 1.5g (5mmol) of triphosgene in 60mL of dichloromethane was added dropwise and stirred at 0 ℃ for 4 hours. And (3) detecting by TLC, after the reaction is finished, dropwise adding 100mL of saturated sodium bicarbonate solution into the reaction solution, quenching, stirring for 10 minutes, separating an organic phase, extracting an aqueous phase by using dichloromethane, combining the organic phases, drying, and spin-drying to obtain a crude product. The crude product was subjected to silica gel column chromatography (eluent: ethyl acetate/petroleum ether-1/1, V/V) to obtain 1.1g of the product as a yellow solid with a yield of 23.1%.1H NMR(400MHz,CDCl3)9.53(s,1H),8.30(s,1H),8.12(s,1H),7.80(d,J＝9.0Hz,1H),3.88–3.75(m,1H),2.76(q,J＝14.8Hz,2H),2.19–2.09(m,2H),2.08–1.95(m,3H),1.71–1.58(m,3H),0.95(s,9H),0.14(s,6H).
Intermediate 221: 8-bromo-1- ((1r,4r) -4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) -3-methyl-1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1.1g (2.3mmol) of intermediate 210 was dissolved in 50mL of dichloromethane, 0.074g (0.23mmol) of tetrabutylammonium bromide and 50mL of a 10% aqueous solution of sodium hydroxide were added, and the mixture was stirred for 10 minutes, 0.98g (6.9mmol) of methyl iodide was added, and the mixture was stirred overnight. And (3) TLC detection, separating an organic phase after the reaction is finished, extracting a water phase by using dichloromethane, combining the organic phases, drying and spin-drying to obtain a crude product. The crude product was subjected to silica gel column chromatography (eluent: ethyl acetate/petroleum ether 1/1, V/V) to obtain 0.4g of the product as a yellow solid in 36.4% yield.
Intermediate 222: 1- ((1r,4r) -4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) -3-methyl-8- (1-phenyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
0.1g (0.2mmol) of intermediate 221 and 0.081g (0.3mmol) of intermediate 4a were dissolved in 10mL of dioxane under nitrogen protection, 0.26g (15.8mmol) of cesium carbonate, 10mL of 2M aqueous sodium carbonate solution, 0.016g (0.02mmol) of [1, 1-bis (diphenylphosphino) ferrocene ] palladium chloride were added, and the mixture was heated at 110 ℃ for 5 hours. And (3) TLC detection, after the reaction is finished, most of dioxane is rotated out, water is added, dichloromethane is used for extraction, organic phases are combined, and the mixture is dried and rotated to obtain a crude product. The crude product was purified on preparative silica gel plate (dichloromethane/methanol-10/1, V/V) to yield 50mg of product as a yellow solid in 45.9% yield.
Batch number Batch (g) Product quantity (g) Yield (%)
022-023 0.1 0.05 45.9
Example 23: 1- ((1r,4r) -4-hydroxycyclohexyl) -3-methyl-8- (1-phenyl-1H-pyrazol-4-yl) -1H- Imidazo [4, 5-c)]Quinolin-2 (3H) -ones
50mg (0.09mmol) of intermediate 222 was dissolved in 20mL of 9% methanolic hydrogen chloride solution and stirred at room temperature for 2 hours. And (3) performing TLC detection, after the reaction is finished, spin-drying the reaction solution, adding 20mL of dichloromethane and 20mL of saturated sodium bicarbonate, stirring for 30 minutes, standing for layering, extracting the aqueous phase with dichloromethane, combining the organic phases, drying, and spin-drying to obtain a crude product. The crude product was purified on preparative silica gel plate (dichloromethane/methanol-10/1, V/V) to give the title compound of example 23 in the form of 20mg as a white solid with a yield of 50.5%. LC-MS 440[ M + 1]]+,tR＝1.674min.1H NMR(400MHz,DMSO)9.12(s,1H),8.82(s,1H),8.35(s,1H),8.28(s,1H),8.09(d,J＝8.8Hz,1H),8.00(d,J＝9.0Hz,1H),7.92(d,J＝7.7Hz,2H),7.56(t,J＝8.0Hz,2H),7.36(t,J＝7.0Hz,1H),4.96–4.67(m,2H),3.57(s,2H),3.47(s,4H),1.97(t,J＝15.8Hz,5H),1.61–1.42(m,3H).
Intermediate 214: 1- ((1r,4r) -4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) -8- (6-methoxy-5-methylpyridin-3-yl) -3-methyl-1H-imidazo [4,5-c ] quinolin-2 (3H) -one
0.1g (0.2mmol) of intermediate 211 and 0.075g (0.3mmol) of intermediate 4b are dissolved in 10mL of dioxane under nitrogen, 0.26g (15.8mmol) of cesium carbonate, 10mL of 2M aqueous sodium carbonate solution and 0.016g (0.02mmol) of [1, 1-bis (diphenylphosphino) ferrocene ] palladium chloride are added and the mixture is heated at 110 ℃ for 5 hours. And (3) TLC detection, after the reaction is finished, most of dioxane is rotated out, water is added, dichloromethane is used for extraction, organic phases are combined, and the mixture is dried and rotated to obtain a crude product. The crude product was purified on preparative silica gel plate (dichloromethane/methanol-10/1, V/V) to yield 70mg of product as a beige solid in 66.0% yield.
Example 24: 1- ((1r,4r) -4-hydroxycyclohexyl) -8- (6-methoxy-5-methylpyridin-3-yl) -3-methyl radical-1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
70mg (0.13mmol) of intermediate 214 was dissolved in 20mL of 9% methanolic hydrogen chloride and stirred at room temperature for 2 hours. And (3) performing TLC detection, after the reaction is finished, spin-drying the reaction solution, adding 20mL of dichloromethane and 20mL of saturated sodium bicarbonate, stirring for 30 minutes, standing for layering, extracting the aqueous phase with dichloromethane, combining the organic phases, drying, and spin-drying to obtain a crude product. The crude product was purified on a preparative silica gel pad (dichloromethane/methanol-10/1, V/V) to obtain 35mg of the title compound of example 24 as a white solid in 64.8% yield. LC-MS 419[ M + 1]]+,tR＝1.628min.1H NMR(400MHz,DMSO)8.87(s,1H),8.49(d,J＝2.3Hz,1H),8.32(s,1H),8.13(d,J＝8.8Hz,1H),8.01(s,1H),7.94(d,J＝8.8Hz,1H),4.87–4.78(m,2H),3.98(s,3H),3.58(s,1H),3.50(s,3H),2.66–2.55(m,2H),2.28(s,3H),2.02(t,J＝14.7Hz,4H),1.47(q,J＝10.4Hz,2H).
Intermediate 216: 1- ((1r,4r) -4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) -3-methyl-8- (6-phenylpyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
0.1g (0.1mmol) of intermediate 211 and 0.042g (0.15mmol) of intermediate 4c are dissolved in 10mL of dioxane under nitrogen, 0.131g (15.8mmol) of cesium carbonate, 10mL of 2M aqueous sodium carbonate solution and 0.008g (0.02mmol) of [1, 1-bis (diphenylphosphino) ferrocene ] palladium chloride are added, and the mixture is heated at 110 ℃ for 5 hours. And (3) TLC detection, after the reaction is finished, most of dioxane is rotated out, water is added, dichloromethane is used for extraction, organic phases are combined, and the mixture is dried and rotated to obtain a crude product. The crude product was purified on preparative silica gel plate (dichloromethane/methanol-10/1, V/V) to yield 20mg of product as a yellow solid in 35.9% yield.
Example 25: 1- ((1r,4r) -4-hydroxycyclohexyl) -3-methyl-8- (6-phenylpyridin-3-yl) -1H-imidazole And [4,5-c ]]Quinolin-2 (3H) -ones
20mg (0.035mmol) of intermediate 216 are dissolved in 20mL of 9% methanolic hydrogen chloride and stirred at room temperature for 2 hours. And (3) performing TLC detection, after the reaction is finished, spin-drying the reaction solution, adding 20mL of dichloromethane and 20mL of saturated sodium bicarbonate, stirring for 30 minutes, standing for layering, extracting the aqueous phase with dichloromethane, combining the organic phases, drying, and spin-drying to obtain a crude product. The crude product was purified on preparative silica gel plate (dichloromethane/methanol-10/1, V/V) to give the title compound of example 25 in 18mg as an off-white solid in yield>100％。LC-MS:452[M+1]+,tR＝1.758min.1H NMR(400MHz,DMSO)9.18(s,1H),8.92(s,1H),8.49(s,1H),8.36(d,J＝8.3Hz,1H),8.30–8.15(m,5H),8.08(d,J＝9.0Hz,1H),7.52(dt,J＝24.9,7.0Hz,3H),5.04–4.71(m,1H),3.64–3.43(m,5H),2.70–2.55(m,3H),2.02(s,4H),1.58–1.39(m,J＝12.8Hz,1H).
(VI) route six:
intermediate 41: (5- (1- ((1s,4s) -4-Hydroxycyclohexyl) -3-methyl-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-8-yl) pyridin-2-yl) carbamic acid tert-butyl ester
Under nitrogen, 0.218g (0.8mmol) of tert-butyl 2-carbamate-5-bromopyridine (intermediate 38), 0.244g (0.96mmol) of pinacol diboron, 0.234g (2.4mmol) of potassium acetate and 0.052g (0.064mmol) of [1, 1-bis (di-phenylphosphino) ferrocene ] palladium chloride were suspended in 15ml of dioxane and heated at 100 ℃ for 2 hours. TLC detection, after the reaction was complete, the crude reaction solution was cooled to room temperature, and 0.2g (0.54mmol) of intermediate 40, 0.9g (2.7mmol) of cesium carbonate, 10ml of dioxane, 10ml of 2M sodium carbonate solution and 0.044g (0.054mmol) of [1, 1-bis (di-phenylphosphino) ferrocene ] palladium chloride were added and heated at 110 ℃ for 5 hours. And (3) TLC detection, after the reaction is finished, most of dioxane is rotated out, water is added, dichloromethane is used for extraction, organic phases are combined, and the mixture is dried and rotated to obtain a crude product. The crude product was purified on preparative silica gel plate (dichloromethane/methanol-10/1, V/V) to yield 240mg of product as a red brown solid in 90.9% yield.
Example 26: 8- (6-Aminopyridin-3-yl) 1- ((1s,4s) -4-hydroxycyclohexyl) -3-methyl-1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
0.24g (0.49mmol) of intermediate 41 was dissolved in 10mL of a dichloromethane/methanol mixed solvent in an ice-water bath, and hydrogen chloride gas was introduced into the reaction solution for thirty minutes. And (3) TLC detection, after the reaction is finished, spin-drying the reaction solution, adding saturated sodium bicarbonate solution to adjust the pH to 8-9, extracting the water phase with dichloromethane, combining the organic phases, drying, and spin-drying to obtain a crude product. The crude product was purified on a preparative silica gel plate (dichloromethane/methanol-10/1, V: V) to yield 0.08g of the title compound of example 26 as an off-white solid in 42.1% yield. LC-MS 390[ M + 1]]+,tR＝1.166min.
(VII) route VII:
intermediate 40 a: (R) -3- ((6-bromo-3-nitroquinolin-4-yl) amino) pyrrolidine-1-carboxylic acid tert-butyl ester
4.28g (14.9mmol) of Compound 3 and 5g (26.8mmol) of Compound 5a were dissolved in 50mL of dichloromethane, and 3.8g (37.3mmol) of triethylamine was added thereto, followed by stirring at room temperature overnight. And (5) detecting by TLC, and after the reaction is finished, spin-drying the solvent to obtain a crude product. The crude product was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate 1/1, V/V) to obtain 6.3g of the product as a yellow powder with a yield of 96.7%. TLC identification coincided with the derotation product in the above example.
Intermediate 41 a: (R) -3- ((3-amino-6-bromoquinolin-4-yl) amino) pyrrolidine-1-carboxylic acid tert-butyl ester
Under an ice-water bath, 6.3g (14.4mmol) of intermediate 40a was dissolved in 50mL of N, N-dimethylformamide. 16.3g (72mmol) of stannous dichloride dihydrate are added in portions over 30 minutes and stirred at room temperature for 2 hours. And (3) detecting by TLC (thin layer chromatography), after the reaction is finished, dropwise adding 10% sodium hydroxide aqueous solution into the reaction solution until the pH value is 8-9, filtering, extracting the filtrate by using dichloromethane, washing a filter cake by using dichloromethane, combining organic phases, washing by using water, washing by using brine, drying, and spin-drying to obtain 8g of a product, namely a reddish brown oily substance, wherein the crude yield is 100%. TLC identification coincided with the derotation product in the above example.
Intermediate 42 a: (R) -3- (8-bromo-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester
Under an ice-water bath, 8g (14.4mmol) of intermediate 41a was dissolved in 50mL of dichloromethane, and 5.8g (57.6mmol) of triethylamine was added thereto and stirred for 10 minutes. A solution of 2.6g (8.64mmol) of triphosgene in 50mL of dichloromethane was added dropwise and stirred at 0 ℃ for 4 hours. And (3) TLC detection, after the reaction is finished, 150mL of saturated sodium bicarbonate solution is added into the reaction solution dropwise for quenching, the stirring is carried out for 10 minutes, an organic phase is separated, a water phase is extracted by dichloromethane, and the organic phase is combined, dried and spin-dried to obtain a crude product. The crude product was subjected to silica gel column chromatography (eluent: dichloromethane/methanol-10/1, V/V) to obtain 0.9g of the product as a brown solid in 14.2% yield. TLC identification coincided with the derotation product in the above example.
Intermediate 43 a: (R) -3- (8-bromo-3-methyl-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester
0.9g (2mmol) of intermediate 42a was dissolved in 50mL of methylene chloride, and 0.064g (0.2mmol) of tetrabutylammonium bromide and 50mL of a 10% aqueous solution of sodium hydroxide were added thereto, followed by stirring for 10 minutes, 0.86g (6mmol) of methyl iodide was added thereto, and the mixture was stirred for 4 hours. And (3) TLC detection, standing for layering after the reaction is finished, separating out an organic phase, extracting an aqueous phase by using dichloromethane, combining the organic phases, drying and spin-drying to obtain 0.9g of a product, namely a yellow solid with the yield of 99.2%. TLC identification coincided with the derotation product in the above example.
Intermediate 44 a: (R) -3- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) piperidin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester
0.9g (2mmol) of intermediate 43a and 1g (3.6mmol) of intermediate 9A were dissolved in 40mL of dioxane under nitrogen, 3.25g (10mmol) of cesium carbonate, 10mL of 2M aqueous sodium carbonate solution and 0.16g (0.2mmol) of [1, 1-bis (diphenylphosphino) ferrocene ] palladium chloride were added, and the mixture was heated at 110 ℃ for 5 hours. And (3) TLC detection, after the reaction is finished, most of dioxane is rotated out, water is added, dichloromethane is used for extraction, organic phases are combined, and the mixture is dried and rotated to obtain a crude product. The crude product was subjected to silica gel column chromatography (dichloromethane/methanol-20/1, V: V) to obtain 1g of the product as a reddish earth solid in 95.2% yield. TLC identification coincided with the derotation product in the above example.
Intermediate 45 a: (R) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one hydrochloride
1g of intermediate 44a was dissolved in 30mL of dichloromethane in an ice-water bath, and hydrogen chloride gas was introduced into the reaction solution for thirty minutes. TLC detection, after the reaction is finished, filtration is carried out, the solid is washed by dichloromethane and is dried by suction under reduced pressure, and 0.7g of a product is obtained and is a tan solid, and the yield is 77.7%. TLC identification coincided with the derotation product in the above example.
Example 27: (R) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) amide Yl) pyrrolidin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
150mg (0.3mmol) of intermediate 45a was dissolved in 10mL of dichloromethane, 152mg (1.5mmol) of triethylamine and 51.5mg (0.45mmol) of methanesulfonyl chloride were added thereto, and the mixture was stirred at room temperature overnight. TLC detection, reverseAfter the reaction, 20mL of saturated aqueous sodium bicarbonate solution was added, the mixture was stirred for 20 minutes, the layers were separated, the aqueous phase was extracted with dichloromethane, and the organic phases were combined, dried, and spin-dried to obtain a crude product. The crude product was purified by preparative silica gel plate (dichloromethane/methanol-10/1, V/V) to obtain 50mg of the title compound of example 27 as an off-white solid in 33.5% yield. TLC and HPLC identification coincided with the derotation product in the above example. LC-MS 504[ M + 1]]+,tR＝1.460min.
(eight) route eight:
intermediate 40 b: (S) -3- ((6-bromo-3-nitroquinolin-4-yl) amino) pyrrolidine-1-carboxylic acid tert-butyl ester
4.28g (14.9mmol) of Compound 3 and 5g (26.8mmol) of Compound 5a were dissolved in 50mL of dichloromethane, and 3.8g (37.3mmol) of triethylamine was added thereto, followed by stirring at room temperature overnight. And (5) detecting by TLC, and after the reaction is finished, spin-drying the solvent to obtain a crude product. The crude product was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate 1/1, V/V) to obtain 6.5g of the product as a yellow powder with a yield of 99.7%. TLC identification coincided with the derotation product in the above example.
Intermediate 41 b: (S) -3- ((3-amino-6-bromoquinolin-4-yl) amino) pyrrolidine-1-carboxylic acid tert-butyl ester
Under an ice-water bath, 6.5g (14.8mmol) of intermediate 40b was dissolved in 50mL of N, N-dimethylformamide. 16.8g (74.2mmol) of stannous dichloride dihydrate are added in portions over 30 minutes and stirred at room temperature for 2 hours. And (3) detecting by TLC (thin layer chromatography), after the reaction is finished, dropwise adding 10% sodium hydroxide aqueous solution into the reaction solution until the pH value is 8-9, filtering, extracting the filtrate by using dichloromethane, washing a filter cake by using dichloromethane, combining organic phases, washing by using water, washing by using brine, drying, and spin-drying to obtain 6.7g of a product, namely a reddish brown oily substance, wherein the crude yield is 100%. TLC identification coincided with the derotation product in the above example.
Intermediate 42 b: (S) -3- (8-bromo-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester
Under an ice-water bath, 6.7g (14.4mmol) of intermediate 41b was dissolved in 50mL of dichloromethane, and 5.8g (57.6mmol) of triethylamine was added thereto and stirred for 10 minutes. A solution of 2.6g (8.64mmol) of triphosgene in 50mL of dichloromethane was added dropwise and stirred at 0 ℃ for 4 hours. And (3) TLC detection, after the reaction is finished, 150mL of saturated sodium bicarbonate solution is added into the reaction solution dropwise for quenching, the stirring is carried out for 10 minutes, an organic phase is separated, a water phase is extracted by dichloromethane, and the organic phase is combined, dried and spin-dried to obtain a crude product. The crude product was subjected to silica gel column chromatography (eluent: dichloromethane/methanol-10/1, V/V) to obtain 4g of product as a brown solid in 62.5% yield. TLC identification coincided with the derotation product in the above example.
Intermediate 43 b: (S) -3- (8-bromo-3-methyl-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester
4g (9mmol) of intermediate 42b was dissolved in 80mL of dichloromethane, 0.29g (0.9mmol) of tetrabutylammonium bromide and 80mL of 10% aqueous sodium hydroxide solution were added, and the mixture was stirred for 10 minutes, 3.46g (27mmol) of methyl iodide was added, and the mixture was stirred for 4 hours. And (3) TLC detection, standing for layering after the reaction is finished, separating out an organic phase, extracting an aqueous phase by using dichloromethane, combining the organic phases, drying and spin-drying to obtain 4.1g of a product, namely a yellow solid with the yield of 100%. TLC identification coincided with the derotation product in the above example.
Intermediate 44 b: (S) -3- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) piperidin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester
3g (6.7mmol) of intermediate 43b and 2.85g (10mmol) of intermediate 9A were dissolved in 100mL of dioxane under nitrogen, 10g (33.5mmol) of cesium carbonate, 20mL of 2M aqueous sodium carbonate solution, 0.55g (0.67mmol) of [1, 1-bis (diphenylphosphino) ferrocene ] palladium chloride were added, and the mixture was heated at 110 ℃ for 5 hours. And (3) TLC detection, after the reaction is finished, most of dioxane is rotated out, water is added, dichloromethane is used for extraction, organic phases are combined, and the mixture is dried and rotated to obtain a crude product. The crude product was subjected to silica gel column chromatography (dichloromethane/methanol-20/1, V: V) to obtain 1.1g of the product as a reddish earth solid in 31.4% yield. TLC identification coincided with the derotation product in the above example.
Intermediate 45 b: (S) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one hydrochloride
1.1g (2.1mmol) of intermediate 44b was dissolved in 30mL of dichloromethane in an ice-water bath, and hydrogen chloride gas was introduced into the reaction solution for thirty minutes. TLC detection, after the reaction is finished, filtration is carried out, the solid is washed by dichloromethane and is dried by suction under reduced pressure, and the product 1.1g is obtained, and is off-white solid, and the crude yield is 100%. TLC identification coincided with the derotation product in the above example.
Example 28: (S) -3-methyl-8- (6- (1-methyl-1H-pyrazole-)4-Yl) pyridin-3-Yl) -1- (1- (methylsulfonyl) Yl) pyrrolidin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
1.1g (2.1mmol) of intermediate 45b was dissolved in 50mL of dichloromethane, 1.07g (10.5mmol) of triethylamine and 0.36g (3.1mmol) of methanesulfonyl chloride were added thereto, and the mixture was stirred at room temperature overnight. And (3) TLC detection, after the reaction is finished, adding 40mL of saturated sodium bicarbonate aqueous solution, stirring for 20 minutes, demixing, extracting the aqueous phase with dichloromethane, combining the organic phases, drying and spin-drying to obtain a crude product. The crude product was subjected to silica gel column chromatography (dichloromethane/methanol-30/1, V: V) to obtain 0.28g of the title compound of example 28 as an off-white solid in 25.4% yield. TLC and HPLC identification coincided with the derotation product in the above example. LC-MS 504[ M + 1]]+,tR＝1.460min.1H NMR(400MHz,CDCl3)8.91(s,1H),8.78(s,1H),8.34(s,1H),8.29(d,J＝8.9Hz,1H),8.10(s,1H),8.04(s,2H),7.93(d,J＝8.6Hz,1H),7.65(d,J＝8.0Hz,1H),5.87–5.72(m,1H),4.11–4.02(m,1H),4.00(s,3H),3.97–3.92(m,1H),3.86–3.81(m,1H),3.63(s,3H),3.61–3.57(m,1H),2.97(s,3H),2.91–2.82(m,1H),2.58–2.44(m,1H).
Example 29: (S) -1- (1- (ethylsulfonyl) pyrrolidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyri-dine Oxazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
0.15g (0.3mmol) of intermediate 45b was dissolved in 25mL of dichloromethane, 0.15g (1.5mmol) of triethylamine was added, and 0.058g (0.45mmol) of ethylsulfonyl chloride was added thereto and stirred at room temperature overnight. TLC detection, after the reaction is finished, 25mL saturated sodium bicarbonate aqueous solution is added, the mixture is stirred for 20 minutes, layers are separated, and the aqueous phase is dichloroExtracting with methane, mixing organic phases, drying, and spin-drying to obtain crude product. The crude product was subjected to silica gel column chromatography (dichloromethane/methanol-30/1, V: V) to obtain 0.12g of the title compound of example 29 as an off-white solid in 77.4% yield. LC-MS 518[ M + 1]]+,tR＝1.572min.1H NMR(400MHz,DMSO)9.04(s,1H),8.94(s,1H),8.52(s,1H),8.37(s,1H),8.28(d,J＝8.3Hz,1H),8.17(d,J＝8.8Hz,1H),8.08(s,1H),8.03(d,J＝8.9Hz,1H),7.78(d,J＝8.2Hz,1H),6.03–5.77(m,1H),4.03–3.82(m,5H),3.71(dd,J＝13.3,8.6Hz,1H),3.63–3.47(m,4H),3.23(q,J＝7.3Hz,2H),2.81–2.67(m,1H),2.48–2.34(m,1H),1.28(t,J＝7.3Hz,3H).
(ninth) route nine:
an intermediate body 910: (S) -3- (3-methyl-2-oxo-8- (6-phenylpiperidin-3-yl) -2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester
Under nitrogen protection, 0.156g (0.67mmol) of 5-bromo-2-phenylpyridine, 0.253g (1mmol) of pinacol diboron, 0.197g (2.01mmol) of potassium acetate and 0.044g (0.05mmol) of [1, 1-bis (di-phenylphosphino) ferrocene]Palladium chloride was dissolved in 10ml dioxane and heated at 100 ℃ for 2 hours. TLC detection, after the reaction was complete, the crude reaction solution was cooled to room temperature and 0.2g (0.45mmol) of intermediate 43b, 0.586g (1.8mmol) of cesium carbonate, 10ml of dioxane, 5ml of 2M sodium carbonate solution and 0.036g (0.045mmol) of [1, 1-bis (diphenylphosphino) ferrocene]Palladium chloride, heated at 110 ℃ for 5 hours. And (3) TLC detection, after the reaction is finished, most of dioxane is rotated out, water is added, dichloromethane is used for extraction, organic phases are combined, and the mixture is dried and rotated to obtain a crude product. The crude product was purified on preparative silica gel plates (dichloromethane/methanol-10/1, V/V) to yield 200mg of product as a tan solid to yieldThe rate was 85.4%. LC-MS 522[ M + 1]]+,tR＝2.446min.
Intermediate 911: (S) -3-methyl-8- (6-phenylpiperidin-3-yl) -1- (pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one hydrochloride
0.2g (0.38mmol) of intermediate 910 was dissolved in 8mL of dichloromethane under an ice-water bath, and hydrogen chloride gas was introduced into the reaction solution for thirty minutes. TLC detection, after the reaction is finished, filtering, washing the solid with dichloromethane, and pumping under reduced pressure to obtain 0.15g of a product, which is a solid in a yellowish brown color and has a yield of 93.8%.
Example 30: (S) -3-methyl-1- (1- (methylsulfonyl) pyrrolidin-3-yl) -8- (6-phenylpyridin-3-yl) - 1H-imidazo [4,5-c ]]Quinolin-2 (3H) -ones
0.15g (0.35mmol) of intermediate 911 was dissolved in 25mL of dichloromethane, 0.192g (1.9mmol) of triethylamine was added, and 0.062g (0.57mmol) of methanesulfonyl chloride was further added, and the mixture was stirred at room temperature overnight. And (3) TLC detection, after the reaction is finished, adding 25mL of saturated sodium bicarbonate aqueous solution, stirring for 20 minutes, demixing, extracting the aqueous phase with dichloromethane, combining the organic phases, drying and spin-drying to obtain a crude product. The crude product was subjected to silica gel column chromatography (dichloromethane/methanol-10/1, V: V) to obtain 0.04g of the title compound of example 30 as a white solid in 22.5% yield. LC-MS 500[ M + 1]]+,tR＝1.929min.
(ten) route ten:
intermediate 50 a: (R) -3- ((6-bromo-3-nitroquinolin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester
4.49g (15.6mmol) of Compound 3 and 5g (24.9mmol) of Compound 4a were dissolved in 50mL of dichloromethane, and 3.2g (31.2mmol) of triethylamine was added thereto, followed by stirring at room temperature overnight. And (5) detecting by TLC, and after the reaction is finished, spin-drying the solvent to obtain a crude product. The crude product was subjected to silica gel column chromatography (eluent: ethyl acetate) to obtain 6.2g of a product as a yellow powder in 88.6% yield. TLC identification coincided with the derotation product in the above example.
Intermediate 51 a: (R) -3- ((3-amino-6-bromoquinolin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester
Under an ice-water bath, 6.2g (13.7mmol) of intermediate 50a was dissolved in 50mL of N, N-dimethylformamide. 15.5g (68.6mmol) of stannous dichloride dihydrate are added in portions over 30 minutes and stirred at room temperature for 2 hours. And (3) detecting by TLC (thin layer chromatography), after the reaction is finished, dropwise adding 10% sodium hydroxide aqueous solution into the reaction solution until the pH value is 8-9, filtering, extracting the filtrate by using dichloromethane, washing a filter cake by using dichloromethane, combining organic phases, washing by using water, washing by using brine, drying, and spin-drying to obtain 6.8g of a product, namely a reddish brown oily substance, wherein the crude yield is 100%. TLC identification coincided with the derotation product in the above example.
Intermediate 52 a: (R) -3- (8-bromo-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) piperidine-1-carboxylic acid tert-butyl ester
Under an ice-water bath, 6.8g (13.7mmol) of intermediate 51a was dissolved in 50mL of dichloromethane, and 5.5g (54.8mmol) of triethylamine was added thereto and stirred for 10 minutes. A solution of 2.4g (8.22mmol) of triphosgene in 50mL of dichloromethane was added dropwise and stirred at 0 ℃ for 4 hours. And (3) TLC detection, after the reaction is finished, 150mL of saturated sodium bicarbonate solution is added into the reaction solution dropwise for quenching, the stirring is carried out for 10 minutes, an organic phase is separated, a water phase is extracted by dichloromethane, and the organic phase is combined, dried and spin-dried to obtain a crude product. The crude product was subjected to silica gel column chromatography (eluent: dichloromethane/methanol-10/1, V/V) to obtain 4.1g of the product as a red brown solid with a yield of 67.5%. TLC identification coincided with the derotation product in the above example.
Intermediate 53 a: (R) -3- (8-bromo-3-methyl-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) piperidine-1-carboxylic acid tert-butyl ester
0.6g (1.34mmol) of intermediate 52a was dissolved in 40mL of dichloromethane, and 0.044g (0.134mmol) of tetrabutylammonium bromide and 40mL of 10% aqueous sodium hydroxide solution were added thereto, followed by stirring for 10 minutes, 0.57g (4mmol) of methyl iodide was added thereto, and the mixture was stirred for 4 hours. And (3) TLC detection, standing and layering after the reaction is finished, separating out an organic phase, extracting a water phase by using dichloromethane, combining the organic phases, drying and spin-drying to obtain 0.7g of a product, namely an orange-red solid with the yield of 100%. TLC identification coincided with the derotation product in the above example.
Intermediate 54 a: (R) -3- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) piperidine-1-carboxylic acid tert-butyl ester
0.7g (1.5mmol) of intermediate 53a and 0.65g (2.3mmol) of intermediate 9A are dissolved in 40mL of dioxane under nitrogen, 2.4g (7.5mmol) of cesium carbonate, 10mL of 2M aqueous sodium carbonate solution and 0.12g (0.15mmol) of [1, 1-bis (diphenylphosphino) ferrocene ] palladium chloride are added, and the mixture is heated at 110 ℃ for 5 hours. And (3) TLC detection, after the reaction is finished, most of dioxane is rotated out, water is added, dichloromethane is used for extraction, organic phases are combined, and the mixture is dried and rotated to obtain a crude product. The crude product was subjected to silica gel column chromatography (dichloromethane/methanol-20/1, V: V) to obtain 0.7g of the product as a reddish earth solid in 87.1% yield. TLC identification coincided with the derotation product in the above example.
Intermediate 55 a: 3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (piperidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
0.7g (1.3mmol) of intermediate 54a was dissolved in 20mL of dichloromethane in an ice-water bath, and hydrogen chloride gas was introduced into the reaction solution for thirty minutes. TLC detection, after the reaction is finished, filtration is carried out, and the solid is washed by dichloromethane and is dried by suction under reduced pressure, so that 0.5g of a product is obtained and is a tan solid with the yield of 71.4%. TLC identification coincided with the derotation product in the above example.
Example 31: (R) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) amide Yl) piperidin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
0.5g (0.97mmol) of intermediate 55a was dissolved in 20mL of dichloromethane, 0.506g (5mmol) of triethylamine and 0.171g (1.5mmol) of methanesulfonyl chloride were added thereto, and the mixture was stirred at room temperature overnight. And (3) TLC detection, after the reaction is finished, adding 20mL of saturated sodium bicarbonate aqueous solution, stirring for 20 minutes, demixing, extracting the aqueous phase with dichloromethane, combining the organic phases, drying and spin-drying to obtain a crude product. Crude product is passed through silica gel columnChromatography (dichloromethane/methanol-10/1, V: V) afforded 0.15g of the title compound of example 31 as an off-white solid in 30.4% yield. TLC and HPLC identification coincided with the derotation product in the above example. LC-MS 518[ M + 1]]+,tR＝1.509min.1H NMR(400MHz,CDCl3)8.95(d,J＝2.0Hz,1H),8.76(s,1H),8.44–8.00(m,5H),7.95(d,J＝8.9Hz,1H),7.69(d,J＝7.8Hz,1H),5.15–5.03(m,1H),4.21(d,J＝8.9Hz,1H),4.02(s,3H),4.00–3.80(m,2H),3.62(s,3H),3.02–2.75(m,5H),2.34–1.83(m,3H).
(eleven) route eleven:
an intermediate 410: 3- ((6-bromo-3-nitroquinolin-4-yl) amino) cyclohexanol
1g (3.48mmol) of Compound 3 and 0.48g (4.17mmol) of 3-aminocyclohexanol (cis-trans isomer mixture) were dissolved in 10ml of dichloromethane, 1.46ml (10.44mmol) of triethylamine was added, and the mixture was stirred at room temperature for 2 hours to precipitate a solid. After the reaction is finished, filtering, washing with a small amount of dichloromethane, draining to obtain 0.4g of yellow solid, passing the mother liquor through a silica gel chromatographic column, and eluting (ethyl acetate: petroleum ether is 1: 10-1.5: 1) to obtain 0.21g of yellow solid, wherein the total amount of yellow solid is 0.61g, and the yield is as follows: 47.89 percent. LC-MS 366,368[ M + 1]]+,tR＝1.978min.
Intermediate 411: 3- ((3-amino-6-bromoquinolin-4-yl) amino) cyclohexanol
0.6g (1.64mmol) of intermediate 410 dissolved in 12ml of ethanol are added portionwise 1.85g (8.20mmol) of stannous chloride dihydrateThe reaction was exothermic and stirred at room temperature overnight. Adding 7ml of 10% sodium hydroxide into a reaction system to adjust the pH value of the system to 8-9, stirring at room temperature for 10min, adding 20ml of dichloromethane and 20ml of water, separating, extracting a water phase with 80ml of dichloromethane for four times, combining organic phases, backwashing with a proper amount of saturated saline solution, drying, filtering, performing rotary evaporation, and performing suction drying to obtain 0.52g of brown crystals, wherein the yield is as follows: 94.30 percent. LC-MS 336,338[ M + 1]]+,tR＝1.509min.
Intermediate 412: 8-bromo-1- (3-hydroxycyclohexyl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
0.51g (1.52mmol) of intermediate 411 is dissolved in 10ml of dichloromethane, 0.64ml (4.56mmol) of triethylamine is added dropwise under the condition of stirring in an ice-water bath, 0.226g (0.76mmol) of triphosgene dissolved in 5ml of dichloromethane is added dropwise, and the reaction is carried out overnight under the condition of stirring in an ice bath. Quench with 30ml of saturated sodium bicarbonate and precipitate a solid. Filtering, and dissolving the solid with a large amount of dichloromethane-methanol mixed solution (1: 1); the phases of the filtrate are separated, the water phase is extracted by 120ml dichloromethane for four times, the organic phases are merged and evaporated in a rotary mode, then ethanol is added for azeotropy to take out the water in the solid, the brown solid is extracted by pumping, and the yield of the crude product is 100%. LC-MS 362,364[ M + 1]]+,tR＝1.509min.
Intermediate 413: 8-bromo-1- (3-hydroxycyclohexyl) -3-methyl-1H-imidazo [4,5-c ] quinolin-2 (3H) -one
0.84g (theoretical yield 0.55g, 1.52mmol) of the crude intermediate 412 obtained in the previous step is dissolved in 20ml of dichloromethane, 0.049g (0.152mmol) of TBAB and 20ml of 10% sodium hydroxide solution are added, stirring is carried out for 10min, 0.28ml (4.56mmol) of methyl iodide is added, and stirring is carried out at room temperature overnight. The reaction was completed, the liquid was separated, the aqueous phase was extracted four times with 80ml of dichloromethane,the combined organic phases were dried and chromatographed on silica gel, and the eluent (methanol: dichloromethane: 1:30 to 1:15) gave 56mg of solid in yield: 9.8 percent. LC-MS 376,378[ M + 1]]+,tR＝1.603min.
Example 32: 1- (3-Hydroxycyclohexyl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3- Radical) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
56mg (0.149mmol) of intermediate 413, 63.7mg (0.224mmol) of compound 9A, 242.7mg (0.745mmol) of cesium carbonate, 0.4ml of a 2M sodium carbonate solution, dissolved in 2ml of dioxane, and after replacing the air with nitrogen, 24.2mg (0.0149mmol) of Pd (dppf) Cl2-CH2Cl2Then, the air was replaced with nitrogen again, and the reaction was carried out for 4 hours at 110 ℃ under nitrogen protection. The starting materials were reacted completely, concentrated by rotary evaporation, 10ml of water and 20ml of dichloromethane were added, the mixture was separated, the aqueous phase was extracted three times with 60ml of dichloromethane, the organic phases were combined, concentrated by rotary evaporation, the solid was dissolved with a small amount of dichloromethane, and the target compound of example 32, racemic, cis-trans isomer mixture, yellow solid 42mg, yield: 62.08 percent. LC-MS:455[ M +1]+,tR＝1.445min.1H NMR(400MHz,DMSO)8.99(d,J＝2.3Hz,1H),8.90(s,1H),8.37(d,J＝12.0Hz,2H),8.21(dd,J＝8.3,2.3Hz,1H),8.17(d,J＝8.8Hz,1H),8.09(s,1H),8.02(d,J＝8.8Hz,1H),7.83(d,J＝8.3Hz,1H),4.96–4.79(m,1H),3.92(s,3H),3.69(d,J＝4.2Hz,1H),3.51(s,3H),3.21–3.07(m,1H),2.44–2.27(m,2H),2.25–2.10(m,1H),2.04–1.72(m,3H),1.66–1.40(m,2H),1.37–1.26(m,1H).
(twelfth) route twelve:
an intermediate 402: ((1s,4s) -4- ((6-bromo-3-nitroquinolin-4 yl) amino) cyclohexyl) carbamic acid tert-butyl ester
0.5g (1.74mmol) of Compound 3 and 0.45g (2.09mmol) of cis tert-butyl N- (4-aminocyclohexyl) carbamate were suspended in 50ml of dichloromethane, 0.73ml (5.22mmol) of triethylamine was added, and the mixture was stirred at room temperature for 2.5 hours to precipitate a solid. Filtration, washing with a small amount of dichloromethane, and suction drying gave 0.6g of a yellow solid with a yield of 74.10%. LC-MS 465,467[ M + 1]]+,tR＝2.601min.
Intermediate 403: ((1s,4s) -4- ((6-bromo-3-aminoquinolin-4 yl) amino) cyclohexyl) carbamic acid tert-butyl ester
0.6g (1.31mmol) of intermediate 402 are dissolved in 5ml of DMF, 1.48g (6.55mmol) of stannous chloride hydrate are added in portions and the mixture is stirred at room temperature for 1 h. Quenching the mixture by 70ml of saturated sodium bicarbonate, stirring, standing, separating phases, respectively extracting the water phase by 70ml, 50ml, 30ml and 30ml of ethyl acetate, combining organic phases, adjusting the pH value of the water phase to be 8-9, drying the water phase by anhydrous sodium sulfate, and evaporating to dryness to obtain brown crystals of 0.51g, wherein the yield is 89.42%. LC-MS 435,437[ M + 1]]+,tR＝1.822min.
Intermediate 404: ((1s,4s) -4- (8-bromo-2-carbonyl-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) cyclohexyl) carbamic acid tert-butyl ester
0.5g (1.15mmol) of intermediate 403 is dissolved in 10ml dichloromethane and added dropwise with stirring in an ice-water bathAdding 0.48ml (3.45mmol), adding 0.171g (0.575mmol) triphosgene dissolved in 2ml dichloromethane, stirring in ice-water bath for 2.5h, adding 24ml saturated sodium bicarbonate dropwise into the reaction solution, stirring, standing, separating, extracting the water phase with 24ml × 2 dichloromethane, combining the organic phases, drying, and spin-drying to obtain crude product, passing the crude product through silica gel chromatography column (eluent: methanol: dichloromethane: 1:15) to obtain yellow solid 0.22g, yield 41.47%. LC-MS:461,463[ M + 1], [ LC-MS: 1], []+,tR＝2.072min.
Intermediate 405: ((1s,4s) -4- (8-bromo-3-methyl-2-carbonyl-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) cyclohexyl) carbamic acid tert-butyl ester
Dissolving 0.22g (0.48mmol) of intermediate 404 in 14ml of dichloromethane, adding 0.015g (0.048mmol) of TBAB, adding 14ml of 10% NaOH, stirring for 10min, adding 0.09ml (1.44mmol) of methyl iodide, stirring at room temperature for reaction overnight (20h), standing the reaction solution, separating, extracting the aqueous phase with 14ml of × 2 dichloromethane, combining the organic phases, drying, rotary steaming for concentration, vacuum pumping to obtain 0.226g of yellow solid, wherein the yield is 99.04% LC-MS (liquid chromatography-mass spectrometry) 475,477[ M + 1] of the yellow solid]+,tR＝2.351min.
An intermediate 406: ((1s,4s) -4- (8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -3-methyl-2-carbonyl-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) cyclohexyl) carbamic acid tert-butyl ester
0.226g (0.48mmol) of intermediate 405,0.205g (0.72mmol) of 9A, 0.782g (2.4mmol) of cesium carbonate are suspended in 7.5ml of dioxane, 1.5ml of 2M sodium carbonate are added, and 0.039g (0.048mmol) of [1,1' -bis (diphenylphosphino) ferrocene are added under nitrogen protection]And (3) carrying out nitrogen protection again on the palladium dichloride dichloromethane complex, and heating to 110 ℃ for reaction for 4 hours. Adding 20ml of water, stirring,then 20ml of dichloromethane was added and stirred, the mixture was allowed to stand for liquid separation, the aqueous phase was extracted with 20ml of × 3 dichloromethane, the organic phases were combined and dried, and the mixture was subjected to silica gel chromatography (eluent: methanol: dichloromethane ═ 1:15) to give 0.223g of a reddish brown solid, yield: 84.72%. LC-MS:554,555[ M +1 ═ M ],]+,tR＝1.884min.
intermediate 407: 1- ((1s,4s) -4-aminocyclohexyl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
0.2g (0.36mmol) of intermediate 406 was added with 8ml of 9.1% methanolic hydrogen chloride, stirred overnight at room temperature to precipitate a solid, which was filtered, washed with 10ml of dichloromethane and dried by suction to give 0.12g of a yellow solid, yield: 63.1 percent. LC-MS 227.5[ M/2+ 1]]+,tR＝1.322min.
Example 33: n- ((1s,4s) -4- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2- Oxo-2, 3-dihydro-1H-imidazo [4,5-c]Quinolin-1-yl) cyclohexyl) acetamides
50mg (0.095mmol) of intermediate 407, 50ml of dichloromethane, 66.2. mu.l of triethylamine, stirring for 15min, dissolving the solid, adding 10.7. mu.l of acetic anhydride, and reacting for 1 h. Rotary evaporation and TLC plates (dichloromethane: methanol 10:1) gave the title compound of example 33 as a white solid, 28mg, yield: 59.49 percent. LC-MS 248.7[ M/2+ 1]]+,tR＝1.509min.1HNMR(400MHz,DMSO)8.99(d,J＝2.3Hz,1H),8.90(s,1H),8.39(s,2H),8.22(dd,J＝8.3,2.4Hz,1H),8.17(d,J＝8.8Hz,1H),8.10(s,1H),8.02(d,J＝8.8Hz,1H),7.94(d,J＝5.7Hz,1H),7.84(d,J＝8.3Hz,1H),4.88(t,J＝11.9Hz,1H),3.92(s,4H),3.51(s,3H),2.74(dd,J＝24.5,12.0Hz,2H),2.05–1.66(m,10H).
Example 34: n- ((1s,4s) -4- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2- Oxo-2, 3-dihydro-1H-imidazo [4,5-c]Quinolin-1-yl) cyclohexyl) methanesulfonamides
50mg (0.095mmol) of intermediate 407, 50ml of dichloromethane, 66.2. mu.l of triethylamine, stirring for 15min, dissolving the solid, adding 12.8. mu.l of methanesulfonyl chloride, and reacting for 3 h. 10ml of saturated sodium bicarbonate, 5ml of dichloromethane and 10ml of saturated brine were added, the layers were separated, the aqueous layer was extracted twice with 40ml of dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate, rotary evaporated and dried by suction to give the title compound of example 34 as an off-white solid (46 mg, yield: 91.1 percent. The compound is dissolved in a mixed solution of dichloromethane and methanol, the pH value is adjusted to 2 by using a methanol solution of hydrogen chloride, and the corresponding hydrochloride is obtained by evaporating the solvent. LC-MS 266.7[ M/2+ 1]]+,tR＝1.510min.1H NMR(400MHz,DMSO+D2O)9.20(s,1H),9.01(s,1H),8.61–8.43(m,3H),8.36(s,2H),8.20(s,1H),8.07(d,J＝8.4Hz,1H),5.01(s,1H),3.92(s,3H),3.59(s,1H),3.54(s,3H),2.94(s,3H),2.77(q,J＝13.3Hz,2H),2.07–1.69(m,6H).
(thirteen) route thirteen:
intermediate 451: (1s,4s) -4-amino-cyclohexanecarboxylic acid methyl ester
At 0 ℃, 1.27ml (17.5mmol) of thionyl chloride is added into 10ml of methanol dropwise, the mixture is stirred for 30min, 1g (7mmol) of compound 450 is added, the mixture is heated to room temperature and stirred for 2 days, the reaction is incomplete, the mixture is heated to reflux, the reaction is carried out for 8h, and the reaction is finished. The reaction solution was evaporated to dryness, taken with dichloromethane and methanol and evaporated to dryness to obtain 1.25g of a solid with a crude product yield of 100%. LC-MS 158[ M + 1]]+,tR＝0.485min。
Intermediate 452: (1s,4s) -4- ((6-bromo-3-nitroquinolin-4-yl) amino) cyclohexanecarboxylic acid methyl ester
Intermediate 451(1.25g,7mmol) was dissolved in 10ml dichloromethane, 1g (3.5mmol) of intermediate 3 and 1.94ml (14mmol) triethylamine were added, stirred at room temperature for 24h, evaporated to dryness to give a crude product, which was chromatographed over silica gel column (eluent: ethyl acetate: petroleum ether 1:2) to give 1.3g yellow solid in 91.0% yield. LC-MS 409[ M + 1]]+,tR＝2.481min。
Intermediate 453: (1s,4s) -4- ((6-bromo-3-aminoquinolin-4-yl) amino) cyclohexanecarboxylic acid methyl ester
Intermediate 452(1.3g,3.18mmol) was dissolved in 15ml of N, N-dimethylformamide, 3.59g (15.9mmol) of water and stannous chloride were added in portions and stirred at room temperature for 2.5 h. The reaction solution was slowly poured into 150ml of dichloromethane and 150ml of saturated sodium bicarbonate, the liquid was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed with an equal amount of saturated brine, the organic phase was dried and evaporated to dryness to obtain 1.3g of a reddish brown solid, and the yield of the crude product was 100%.
Intermediate 454: (1s,4s) -4- (8-bromo-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) cyclohexanecarboxylic acid methyl ester
Intermediate 453(1.3g, 3.18mmol) was dissolved in 10ml of dichloromethane, 1.3ml (9.54mmol) of triethylamine was added, and a solution of 0.47g (1.59mmol) of triphosgene in 10ml of dichloromethane was added dropwise under ice-bath cooling, and the reaction was maintained at 0 ℃ for 2 hours after the addition. And pouring 20ml of saturated sodium bicarbonate solution for quenching, separating liquid, extracting an aqueous phase with dichloromethane, combining organic phases, drying, evaporating to obtain a crude product, and performing silica gel column chromatography on the crude product (eluent: methanol: dichloromethane ═ 1:20) to obtain 0.851g of yellow solid with the yield of 66.20%. LC-MS 405[ M + 1]]+,tR＝1.921min。
Intermediate 455: (1s,4s) -4- (8-bromo-3-methyl-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) cyclohexanecarboxylic acid methyl ester
The intermediate 454(0.851g,2.1mmol) was dissolved in 10ml of dichloromethane, 0.068g (0.21mmol) of tetra-n-butylammonium bromide, 10ml of 10% sodium hydroxide solution, and 0.89ml (6.3mmol) of methyl iodide were added, stirred at room temperature overnight, separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried, evaporated to dryness to give a crude product, which was chromatographed on a silica gel column (eluent: methanol: dichloromethane ═ 1:30) to give 0.513g of a yellow solid with a yield of 58.43%. LC-MS 419[ M + 1]]+,tR＝2.102min。
Intermediate 456: (1s,4s) -4- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) cyclohexanecarboxylic acid methyl ester
Intermediate 455(0.513g,1.23mmol) was dissolved in 10ml of 1, 4-bisIn a hexacyclic oxide ring, 0.525g (1.84mmol) of intermediate 9A, 1.6g (4.9mmol) of cesium carbonate, 0.5ml of water, 0.098g (0.12mmol) of [1, 1-bis (di-phenylphosphino) ferrocene are added under nitrogen protection]Heating the palladium chloride to 110 ℃, reacting for 5h, and cooling to room temperature. Dioxane was evaporated off, dissolved in 40ml water and 40ml dichloromethane, the liquid was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried and evaporated to dryness to give a crude product, which was chromatographed on silica gel column (eluent: methanol: dichloromethane ═ 1:20) to give 0.42g of a solid in 68.73% yield. LC-MS:249[ M/2+ 1]]+,tR＝1.739min。
Example 35: (1s,4s) -4- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo 2, 3-dihydro-1H-imidazo [4,5-c ] s]Quinolin-1-yl) cyclohexanecarboxylic acids
Intermediate 456(0.1g,0.2mmol) was dissolved in 10ml of 1, 4-dioxane, 2ml of 10% sodium hydroxide solution was added, stirred at room temperature for 2 days, 100ml of dichloromethane and 100ml of water were added, liquid separation was performed, the pH of the aqueous phase was adjusted to 5 with 1mol/L hydrochloric acid, the aqueous phase was extracted with methyl tert-butyl ether, the organic phases were combined, dried and evaporated to dryness to obtain a crude product, which was subjected to silica gel column chromatography (eluent: methanol: dichloromethane ═ 1:10) to give the title compound of example 35, 0.054g of a solid, with a yield of 56.25%. LC-MS:242[ M/2+1]+,tR＝1.539min。1H NMR(400MHz,DMSO)12.31(s,1H),8.99(s,1H),8.87(s,1H),8.38(s,2H),8.29–7.92(m,4H),7.83(d,J＝7.8Hz,1H),4.88(s,1H),3.92(s,3H),3.47(s,3H),2.82–2.55(m,3H),2.28(d,J＝12.0Hz,2H),1.94(d,J＝11.0Hz,2H),1.76(s,2H).
(fourteen) route fourteen:
intermediate 53 b: 3- (8-bromo-3-deuterated methyl-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) piperidine-1-carboxylic acid tert-butyl ester
0.6g (1.34mmol) of intermediate 108 was dissolved in 30mL of dichloromethane, and 0.044g (0.134mmol) of tetrabutylammonium bromide and 30mL of 10% aqueous sodium hydroxide solution were added thereto, followed by stirring for 10 minutes, 0.78g (4mmol) of deuterated iodomethane was added thereto, and the mixture was stirred for 4 hours. And (3) TLC detection, standing for layering after the reaction is finished, separating an organic phase, extracting a water phase by using dichloromethane, combining the organic phases, drying and spin-drying to obtain a crude product. The crude product was subjected to silica gel column chromatography (dichloromethane/methanol-50/1, V: V) to obtain 0.5g of the product as a white solid in 80.5% yield. LC-MS 464,466[ M + 1]]+,tR＝2.411min.
Intermediate 54 b: 3- (3-deuterated methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-hydro-1H-imidazo [4,5-c ] quinolin-1-yl) piperidine-1-carboxylic acid tert-butyl ester
0.5g (1.1mmol) of intermediate 53b and 0.46g (1.6mmol) of intermediate 9A are dissolved in 40mL of dioxane under nitrogen, 1.8g (5.5mmol) of cesium carbonate, 15mL of 2M aqueous sodium carbonate solution and 0.09g (0.11mmol) of [1, 1-bis (diphenylphosphino) ferrocene]Palladium chloride was heated at 110 ℃ for 5 hours. And (3) TLC detection, after the reaction is finished, most of dioxane is rotated out, water is added, dichloromethane is used for extraction, organic phases are combined, and the mixture is dried and rotated to obtain a crude product. The crude product was subjected to silica gel column chromatography (dichloromethane/methanol-30/1, V: V) to obtain 0.3g of the product as a white solid in 50.3% yield. LC-MS:543[ M + 1]]+,tR＝1.931min.
Intermediate 55 b: 3-deuterated methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (piperidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
0.3g (0.55mmol) of intermediate 54b was dissolved in 20mL of dichloromethane in an ice-water bath, and hydrogen chloride gas was introduced into the reaction solution for thirty minutes. TLC detection, after the reaction is finished, filtering, washing the solid with dichloromethane, and performing vacuum suction drying to obtain 0.3g of a product, a tan solid and a crude product yield of 100%.
Example 36: 3-deuterated methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) amide Yl) piperidin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
0.3g (0.55mmol) of intermediate 55b was dissolved in 40mL of dichloromethane, 0.278g (2.75mmol) of triethylamine was added, and 0.095g (0.825mmol) of methanesulfonyl chloride was further added, and the mixture was stirred at room temperature overnight. And (3) TLC detection, after the reaction is finished, adding 40mL of saturated sodium bicarbonate aqueous solution, stirring for 20 minutes, demixing, extracting the aqueous phase with dichloromethane, combining the organic phases, drying and spin-drying to obtain a crude product. The crude product was subjected to silica gel column chromatography (dichloromethane/methanol-10/1, V: V) to obtain 0.2g of the title compound of example 36 as a pale yellowish white solid in 69.9% yield. LC-MS 521[ M + 1]]+,tR＝1.658min.1H NMR(400MHz,DMSO)8.99(d,J＝2.3Hz,1H),8.93(s,1H),8.40(s,2H),8.24(dd,J＝8.3,2.4Hz,1H),8.19(d,J＝8.9Hz,1H),8.09(s,1H),8.05(d,J＝8.9Hz,1H),7.78(d,J＝8.3Hz,1H),5.07(t,J＝11.4Hz,1H),4.01(d,J＝9.1Hz,1H),3.92(s,3H),3.71(d,J＝10.7Hz,1H),3.58(t,J＝11.4Hz,1H),2.99(s,3H),2.89–2.67(m,2H),2.17(d,J＝11.7Hz,1H),1.99(d,J＝13.3Hz,1H),1.79(q,J＝12.5Hz,1H).
(fifteen) route fifteen:
intermediate 1201: 5- (((6-chloropyridin-3 yl) amino-methylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione
5g (38.8mmol) of 2-chloro-5-aminopyridine and 7.2g (38.8mmol) of 5- (methoxymethyl-ene) -2, 2-dimethyl-1, 3-dioxo-4, 6-dione are suspended in 100mL of isopropanol and heated to reflux for 2 hours. TLC detection, after the reaction is finished, the solvent is dried by spinning, and 10.5g of a product is obtained and is a light yellow white solid, and the yield is 95.8%. LC-MS 283[ M + 1]]+,tR＝1.775min.
Intermediate 1202: 6-chloro-1, 5-naphthyridin-4-ol
500mL of a biphenyl-biphenyl ether mixed solvent was heated to 220 ℃ and 10.5g (37.1mmol) of intermediate 1201 was added to the solvent in portions, followed by stirring at 220 ℃ for 5 minutes after the addition was completed. After the reaction is finished, cooling to room temperature, adding 1L of petroleum ether into the reaction solution, separating out a large amount of solid, filtering, collecting precipitate, washing with petroleum ether, and drying under reduced pressure to obtain 4.9g of a product, namely a yellowish brown solid with the yield of 73.1%. LC-MS 181[ M + 1]]+,tR＝0.583min.
Intermediate 1203: 6-chloro-3-nitro-1, 5-naphthyridin-4-ol
Under an ice-water bath, 4.9g (27.1mmol) of intermediate 1202 and 5.5g (54.2mmol) of potassium nitrate were slowly added to 40mL of concentrated sulfuric acid, and reacted at 100 ℃ for 1 hour. And (3) detecting by TLC, cooling to room temperature after the reaction is finished, slowly pouring the reaction liquid into ice water to separate out a large amount of solid, filtering, collecting precipitate, and drying under reduced pressure to obtain 4.2g of a product, namely a yellow solid, wherein the yield is 63.6%. LC-MS 226[ M + 1]]+,tR＝1.428min.
The intermediate 1204: 2, 8-dichloro-7-nitro-1, 5-naphthyridine
4.2g (17.2mmol) of intermediate 1203 are suspended in 15mL of DMF, a solution of 3.5g (22.4mmol) of phosphorus oxychloride in 10 catalogue of DMF is added, the solution is added dropwise over 3 minutes, and after the dropwise addition, the mixture is stirred at room temperature for 20 hours. Pouring the reaction solution into ice water, performing suction filtration, and drying to obtain a soil solid 3.8g, wherein the yield is 90.5%. LC-MS 244[ M + 1]]+,tR＝2.066min.
Intermediate 1205: 3- ((6-chloro-3-nitro-1, 5-naphthyridin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester
0.9g (3.7mmol) of intermediate 1204 and 1.1g (5.6mmol) of the compound 1-tert-butoxycarbonyl-3-aminopiperidine were dissolved in 60mL of dichloromethane, and 0.75g (7.4mmol) of triethylamine was added thereto and the mixture was stirred at room temperature overnight. And (5) detecting by TLC, and after the reaction is finished, spin-drying the solvent to obtain a crude product. The crude product was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate 1/1, V/V) to obtain 1.3g of the product as a yellow powder with a yield of 86.6%. LC-MS 408[ M + 1]]+,tR＝2.603min.
Intermediate 1206: 3- ((3-amino-6-chloro-1, 5-naphthyridin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester
Under an ice-water bath, 1.3g (3.2mmol) of intermediate 1205 was dissolved in 15mL of N, N-dimethylformamide. 3.6g (16mmol) of stannous dichloride dihydrate are added portionwise over 30 minutes and stirred at room temperature for 2 hours. TLC detection, after the reaction is finished, 10% sodium hydroxide aqueous solution is dripped into the reaction liquid to the pH value of 8-9, filtration is carried out, filtrate is extracted by dichloromethane, filter cake is washed by dichloromethane, organic phases are combined, washed by water, washed by brine, dried and dried by spinning to obtain 2.5g of product, reddish brown oily matter with yield>100％。LC-MS:378[M+1]+,tR＝1.758min.
Intermediate 1207: 3- (8-chloro-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] [1,5] naphthyridin-1-yl) piperidine-1-carboxylic acid tert-butyl ester
2.5g (3.2mmol) of intermediate 1206 were dissolved in 10mL of dichloromethane in an ice-water bath, 1.1g (11.2mmol) of triethylamine was added, and the mixture was stirred for 10 minutes. A solution of 0.5g (1.6mmol) of triphosgene in 10mL of dichloromethane was added dropwise and stirred at 0 ℃ for 4 hours. And (3) detecting by TLC, after the reaction is finished, dropwise adding 20mL of saturated sodium bicarbonate solution into the reaction solution, quenching, stirring for 10 minutes, separating an organic phase, extracting an aqueous phase by using dichloromethane, combining the organic phases, drying and spin-drying to obtain a crude product. The crude product was subjected to silica gel column chromatography (eluent: dichloromethane/methanol-40/1, V/V) to obtain 0.4g of the product as a tan solid in 31.8% yield. LC-MS:404[ M + 1]]+,tR＝2.252min.
Intermediate 1208: 3- (8-bromo-3-methyl-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] [1,5] naphthyridin-1-yl) piperidine-1-carboxylic acid tert-butyl ester
0.4g (1mmol) of intermediate 1207 was dissolved in 30mL of dichloromethane, and 0.032g (0.1mmol) of tetrabutylammonium bromide and 30mL of a 10% aqueous solution of sodium hydroxide were added thereto, followed by stirring for 10 minutes, 0.4g (3mmol) of methyl iodide was added thereto, and the mixture was stirred for 4 hours. And (3) TLC detection, standing for layering after the reaction is finished, separating out an organic phase, extracting an aqueous phase by using dichloromethane, combining the organic phases, drying and spin-drying to obtain 0.5g of a product, a yellow solid and a crude product yield of 100%. LC-MS 418[ M + 1]]+,tR＝2.425min.
Intermediate 1209: 3- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] [1,5] naphthyridin-1-yl) piperidine-1-carboxylic acid tert-butyl ester
0.5g (1.2mmol) of intermediate 1208 and 0.5g (1.8mmol) of intermediate 9A are dissolved in 30mL of dioxane under nitrogen, 1.9g (6mmol) of cesium carbonate, 10mL of 2M aqueous sodium carbonate solution are added, and 0.1g (0.12mmol) of [1, 1-bis (di-phenylphosphino) ferrocene are added]Palladium chloride was heated at 110 ℃ for 20 hours. And (3) TLC detection, after the reaction is finished, most of dioxane is rotated out, water is added, dichloromethane is used for extraction, organic phases are combined, and the mixture is dried and rotated to obtain a crude product. The crude product was subjected to silica gel column chromatography (dichloromethane/methanol-40/1, V: V) to obtain 0.6g of the product as a yellowish solid in 92.6% yield. LC-MS 541[ M + 1]]+,tR＝2.095min.
Intermediate 1210: 3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (piperidin-3-yl) -1H-imidazo [4,5-c ] [1,5] naphthyridin-2 (3H) -one
0.2g (0.37mmol) of intermediate 1209 was dissolved in 5mL of dichloromethane in an ice-water bath, and hydrogen chloride gas was introduced into the reaction solution for thirty minutes. TLC detection, after the reaction is finished, filtering, washing the solid with dichloromethane, and carrying out vacuum suction drying to obtain 0.2g of a product, which is a yellowish solid and has a crude product yield of 100%.
Example 37: 3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) Piperidin-3-yl) -1H-imidazo [4,5-c][1,5]Naphthyridin-2 (3H) -ones
0.2g (0.37mmol) of intermediate 1210 was dissolved in 25mL of methylene chloride, 0.187g (1.85mmol) of triethylamine was added, and 0.064g (0.56mmol) of methanesulfonyl chloride was further added, and the mixture was stirred at room temperature overnight. And (3) TLC detection, after the reaction is finished, adding 25mL of saturated sodium bicarbonate aqueous solution, stirring for 20 minutes, demixing, extracting the aqueous phase with dichloromethane, combining the organic phases, drying and spin-drying to obtain a crude product. The crude product was subjected to silica gel column chromatography (dichloromethane/methanol-10/1, V: V) to obtain 0.09g of the title compound of example 37 as a yellow solid in 47.1% yield. LC-MS 519[ M + 1]]+,tR＝1.726min.1H NMR(400MHz,DMSO)9.36(d,J＝1.8Hz,1H),8.99(s,1H),8.59(d,J＝8.1Hz,1H),8.53(d,J＝8.9Hz,1H),8.43(s,1H),8.36(d,J＝8.9Hz,1H),8.11(s,1H),7.81(d,J＝8.4Hz,1H),6.24(br s,1H),3.93(s,3H),3.87(s,1H),3.73(d,J＝11.2Hz,2H),3.55(s,3H),2.97(s,3H),2.84(t,J＝11.9Hz,1H),2.68(s,1H),2.06(d,J＝13.2Hz,2H),1.73(d,J＝12.5Hz,1H).
(sixteen) routes sixteen:
intermediate 421: (S) -3- ((6-chloro-3-nitro-1, 5-naphthyridin-4-yl) amino) pyrrolidine-1-carboxylic acid tert-butyl ester
0.8g (3.28mmol) of compound 1204 and 0.733g (3.94mmol) of compound 5b were dissolved in 15ml of DMF, and after stirring for 10min, 0.92ml of triethylamine was added, and the mixture was stirred at room temperature overnight. 75ml of water is dripped to separate out solid, the solid is filtered, 20ml of water is used for leaching filter cakes, and the filter cakes are dried in vacuum to obtain 1.067g of red solid with the yield of 82.6 percent. LC-MS 393.9[ M + 1]]+,tR＝2.541min.
Intermediate 422: (S) -3- ((3-amino-6-chloro-1, 5-naphthyridin-4-yl) amino) pyrrolidine-1-carboxylic acid tert-butyl ester
1.05g (2.67mmol) of intermediate 421 are dissolved in 20ml DMF, and 3.01g (13.35mmol) of stannous chloride dihydrate are added in portions under ice-water bath conditions and stirred overnight. After the reaction is finished, 10ml of saturated sodium bicarbonate and 8ml of 10% sodium hydroxide are added to adjust the pH value to 8-9, tin salt is removed through filtration, filter cakes are washed 5 times by 100ml of dichloromethane until no 365nm fluorescence exists in the filtrate, standing and liquid separation are carried out, an aqueous phase is extracted three times by 60ml of dichloromethane, organic phases are combined, water and saturated salt water which are equal in volume are used for carrying out back extraction for 2 times respectively, the organic phases are dried, rotary evaporation is carried out, and suction drying is carried out to obtain 0.824g of brown crystals, wherein the yield is 84.82%. LC-MS 363.9[ M + 1]]+,tR＝1.791min.
Intermediate 423: (S) -3- (8-chloro-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] [1,5] naphthyridin-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester
0.82g (2.25mmol) of intermediate 422 in 20ml of dichloromethane, 0.94ml (6.75mmol) of triethylamine dropwise added under stirring in an ice-water bath, and 0.335g (1.13mmol) in 1 dropwise addedTriphosgene in 0ml dichloromethane was stirred under ice bath conditions and reacted overnight. After quenching with 30ml of saturated sodium bicarbonate, the phases were separated, the aqueous phase was extracted three times with 90ml of dichloromethane, the organic phases were combined, dried and the organic phase was chromatographed on silica gel (eluent: methanol: dichloromethane ═ 1:30) to give 0.628g of a brown solid with a yield of 71.6%. LC-MS 389.9[ M + 1]]+,tR＝2.072min.
Intermediate 424: (S) -3- (8-chloro-3-methyl-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] [1,5] naphthyridin-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester
Dissolving 0.62g (1.59mmol) of intermediate 423 in 25ml of dichloromethane, adding 0.053g (0.159mmol) of TBAB, adding 25ml of 10% NaOH, stirring for 10min, adding 0.31ml (4.95mmol) of methyl iodide, stirring at room temperature for reaction overnight, standing the reaction solution, separating liquid, extracting the aqueous phase with 25ml × 4 dichloromethane, combining the organic phases, drying, rotary evaporation and concentration, and vacuum pumping to obtain 0.696g of crude brown solid with the yield of 100%. LC-MS:403.9[ M + 1% ] [ M ]/(M + 1) ]]+,tR＝2.320min.
Intermediate 425: (S) -3- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] [1,5] naphthyridin-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester
0.2g (0.495mmol) of intermediate 424,0.22g (0.77mmol) of 9A, 0.836g (2.565mmol) of cesium carbonate suspended in 15ml of dioxane, 3ml of 2M sodium carbonate and 0.042g (0.051mmol) of [1,1' -bis (diphenylphosphino) ferrocene are added under nitrogen protection]Palladium dichloride dichloromethane complex, protected again with nitrogen, was allowed to warm to 110 ℃ and reacted overnight (15 h). After the reaction is finished, performing rotary evaporation and concentration, adding 25ml of water, stirring, adding 20ml of dichloromethane, stirring, standing and separating liquid,the aqueous phase was extracted with 20ml × 4 dichloromethane, the organic phases combined, dried and chromatographed on silica gel (eluent: methanol: dichloromethane ═ 1:30) to give 0.252g of yellow solid in 96.68% yield LC-MS:526.9[ M +1 ═ 1:]+,tR＝2.103min.
intermediate 426: (S) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (pyrrolidin-3-yl) -1H-imidazo [4,5-c ] [1,5] naphthyridin-2 (3H) -one
0.25g (0.47mmol) of the intermediate 425 is dissolved in 8ml of DCM ice-water bath, HCl gas is introduced, the reaction is stirred for 1h, solid is separated out, the solid is filtered, a small amount of DCM is washed, and the brown solid 0.131g is obtained after vacuum pumping, and the yield is 65.31%. LC-MS 426.9[ M + 1]]+,tR＝1.445min.
Example 38: (S) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) amide Yl) pyrrolidin-3-yl) -1H-imidazo [4,5-c][1,5]Naphthyridin-2 (3H) -ones
130mg (0.30mmol) of intermediate 426, 25ml of dichloromethane, 1.51ml of triethylamine and stirring for 10min, wherein the solid is not completely dissolved, 0.08ml of methyl benzenesulfonyl chloride is added, the reaction is carried out overnight, 25ml of saturated sodium bicarbonate is added, liquid separation is carried out, the water phase is extracted by 35ml of × 3 dichloromethane, the organic phase is combined, dried by anhydrous sodium sulfate and subjected to TLC to prepare a chromatographic plate, and light yellow solid 57mg is obtained, the yield is 37.65%, LC-MS is 504.9[ M + 1] (]+,tR＝1.695min.1HNMR(400MHz,DMSO)9.37(s,1H),9.01(s,1H),8.63(d,J＝8.3Hz,1H),8.53(d,J＝9.0Hz,1H),8.44–8.32(m,2H),8.09(s,1H),7.82(d,J＝8.3Hz,1H),6.74–6.43(m,1H),4.02–3.94(m,1H),3.92(s,3H),3.83(t,J＝9.3Hz,1H),3.73–3.63(m,1H),3.56(s,3H),3.54–3.48(m,1H),3.06(s,3H),2.97–2.82(m,1H),2.45–2.35(m,1H).
(seventeenth) route seventeen:
intermediate 428: (S) -3- (3-methyl-2-oxo-8- (6-phenylpyridin-3-yl) -2, 3-dihydro-1H-imidazo [4,5-c ] [1,5] naphthyridin-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester
156mg (0.67mmol) of the compound 888, 253mg (1mmol) of the diboronic acid ester, 197mg (2.01mmol) of potassium acetate are dissolved in 10ml of dioxane, and 44mg (0.05mmol) of [1,1' -bis (diphenylphosphino) ferrocene are added under nitrogen protection]And (3) adding a palladium dichloride dichloromethane complex into nitrogen for protection, heating to 100 ℃, and stirring for 2 hours. After cooling, 0.2g (0.495mmol) of intermediate 424, 0.806g (2.475mmol) of cesium carbonate, 10ml of dioxane were added, 3ml of 2M sodium carbonate were added, and 0.041g (0.050mmol) of [1,1' -bis (diphenylphosphino) ferrocene were added under nitrogen protection]Heating palladium dichloride dichloromethane complex to 110 ℃, reacting overnight, performing rotary evaporation and concentration, adding 25ml of water, stirring, adding 20ml of dichloromethane, stirring, standing, separating liquid, extracting an aqueous phase with 20ml of × 4 dichloromethane, combining organic phases, drying, and passing through a silica gel chromatographic column (eluent: methanol: dichloromethane ═ 1:40) to obtain 0.286g of yellow solid, wherein the yield is 100 percent, LC-MS:522.9[ M + 1:40 ]]+,tR＝2.789min.
Intermediate 429: (S) -3-methyl-8- (6-phenylpyridin-3-yl) -1- (pyrrolidin-3-yl) -1H-imidazo [4,5-c ] [1,5] naphthyridin-2 (3H) -one
0.28g (0.47mmol) of intermediate 428 was dissolved in 8ml of DCM under ice-water bath and HCl gas was introduced, and the reaction was stirred for 1h to precipitate a solid. The reaction was completed and vacuum-dried to obtain crude brown solid 0.342g with 100% yield.
Example 39: (S) -3-methyl-1- (1- (methylsulfonyl) pyrrolidin-3-yl) -8- (6-phenylpyridin-3-yl) - 1H-imidazo [4,5-c ]][1,5]Naphthyridin-2 (3H) -ones
226mg (0.30mmol) of intermediate 429, 10ml of dichloromethane and 0.4ml of triethylamine are added, stirring is carried out for 10min, the solution is clear, 0.06ml of methyl benzenesulfonyl chloride is added, the reaction is carried out overnight, 10ml of saturated sodium bicarbonate is added, liquid separation is carried out, the water phase is extracted by 20ml of × 3 dichloromethane, the organic phase is combined, dried by anhydrous sodium sulfate and subjected to TLC to prepare a chromatographic plate, and light yellow solid 43mg is obtained, the yield is 16.03%, LC-MS is 500.8[ M + 1]]+,tR＝2.135min.1H NMR(400MHz,DMSO)9.54(s,1H),9.04(s,1H),8.78(d,J＝6.7Hz,1H),8.57(d,J＝8.9Hz,1H),8.45(d,J＝9.6Hz,1H),8.26–8.13(m,3H),7.63–7.45(m,3H),6.60–6.46(m,1H),4.07–3.64(m,3H),3.57(s,3H),3.55–3.48(m,1H),3.07(s,3H),2.99–2.86(m,1H),2.44–2.30(m,1H).
Eighteen route
Example 40: 2-methyl-2- (4- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2- Oxo-2, 3-dihydro-1H-imidazo [4,5-c]Quinolin-1-yl) phenyl) propionamide
Suspending 100mg (0.167mmol) of intermediate 501 in 1ml of water, adding 1ml of concentrated sulfuric acid dropwise, dissolving completely, heating to 100 deg.C, stirring for 2h, cooling to room temperature, and slowly adding 60ml of cold saturated NaHCO dropwise3The reaction mixture was dissolved in 3 × 50ml of dichloromethane methanol (DCM: MeOH ═ 10:1), the organic phases were combined, dried over anhydrous sodium sulfate, and the solid obtained by evaporation was thoroughly stirred with about 15ml of dichloromethane methanol mixed solution (DCM: MeOH ═ 50:1), filtered by suction to give about 70mg of white solid, which was purified with preparative silica gel plate (developing solvent DCM: MeOH ═ 8:1) to give 24mg of white powder]+,tR＝1.601min.1H NMR(400MHz,DMSO)9.01(s,1H),8.47(d,J＝1.9Hz,1H),8.29(s,1H),8.12(d,J＝8.9Hz,1H),8.05–7.94(m,2H),7.65(dd,J＝21.8,8.5Hz,6H),7.29–7.18(m,2H),7.15(s,1H),3.91(s,3H),3.61(s,3H),1.60(s,6H).
Example 41: 2-methyl-2- (4- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2- Oxo-2, 3-dihydro-1H-imidazo [4,5-c]Quinolin-1-yl) phenyl) propanoic acid
Suspending 100mg (0.167mmol) of intermediate 501 in 1ml of water, dropwise adding 1ml of concentrated sulfuric acid, dissolving completely, heating to 150 ℃, stirring for 5h, cooling to room temperature, and slowly dropwise adding 30ml of saturated NaHCO3Adjusting pH to 4-5 with hydrochloric acid, extracting with 4 × ml dichloromethane-methanol mixed solvent (DCM: MeOH ═ 10:1), mixing organic phases, drying with anhydrous sodium sulfate, evaporating to dryness, and purifying with silica gel plate (developing agent DCM: MeOH ═ 8:1) to obtain white powder 20mg]+,tR＝1.728min.1H NMR(400MHz,DMSO)12.53(s,1H),9.02(s,1H),8.54(s,1H),8.28(s,1H),8.13(d,J＝8.9Hz,1H),8.03–7.97(m,2H),7.81–7.51(m,6H),7.19(d,J＝1.9Hz,1H),3.92(s,3H),3.62(s,3H),1.65(s,6H).
Nineteen routes
Intermediate 432: 3- (6-bromo-3-nitroquinolin-4-yl) aminocyclopentanol
1.69g (5.9mmol) of Compound 3 and 1.226g (8.9mmol) of 3-aminocyclopentanol hydrochloride (cis-trans mixture) are dissolved in 20ml of dichloromethane, 3.3ml (23.6mmol) of triethylamine are added and stirring is carried out at room temperature for 2.5h, whereupon a solid precipitates. Filtration, washing with a small amount of dichloromethane, and suction drying gave 2.154g of a yellow solid in 100% yield. LC-MS 351.8,353.8[ M + 1]]+,tR＝1.822min.
Intermediate 433: 3- (6-bromo-3-aminoquinolin-4-yl) aminocyclopentanol
1g (2.84mmol) of intermediate 432 is dissolved in 20ml ethanol, 3.2g (14.2mmol) of stannous chloride dihydrate are added in portions under ice-water bath conditions, and the mixture is stirred overnight. TLC shows that the reaction is finished, 11ml of 10% sodium hydroxide is added to adjust the pH value to 8-9, a large amount of solid is separated out, the solid is filtered, 180ml of ethyl acetate is used for washing a filter cake for 8 times until the filtrate is free from fluorescence, 50ml of water is added, standing and liquid separation are carried out, the water phase is extracted twice by 100ml of ethyl acetate, the organic phases are combined, the organic phases are dried, rotary evaporation is carried out, and pumping is carried out to obtain 0.681g of brown crystals, and the yield is 74.44%. LC-MS 321.9,323.9[ M + 1]]+,tR＝1.385min&1.478min (cis-trans isomer mixture).
Intermediate 434: 8-bromo-1- (3-hydroxycyclopentanyl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
0.675g (2.09mmol) of intermediate 433 dissolved in 20ml of dichloromethane was added dropwise under stirring in an ice-water bath, followed by stirring for 10min, then 0.311g (1.05mmol) of triphosgene dissolved in 10ml of dichloromethane was added dropwise, followed by stirring in an ice bath, followed by reaction for 4 hours. Adding 30ml of saturated sodium bicarbonate for quenching, adding 10ml of methanol until the solid is dissolved, separating, extracting the water phase with 160ml of dichloromethane for four times, combining the organic phases, drying, and passing the organic phases through a silica gel chromatographic column (eluent: methanol: dichloromethane ═ 1:30) to obtain 0.455g of brown solid with the yield of 62.52%. LC-MS 347.8,349.8[ M + 1]]+,tR＝1.385min&1.509min (cis-trans isomer mixture).
Intermediate 435: 8-bromo-3-methyl-1- (3-hydroxycyclopentanyl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
Dissolving 0.45g (1.29mmol) of intermediate 434 in 20ml of dichloromethane, adding 0.042g (0.129mmol) of TBAB, adding 20ml of 10% NaOH, stirring for 10min, adding 0.24ml (3.87mmol) of methyl iodide, stirring at room temperature for reaction overnight, standing the reaction solution, separating the solution, extracting the aqueous phase with 4 × 20ml of dichloromethane, combining the organic phases, drying, rotary evaporating for concentration, and vacuum pumping to obtain 0.442g of crude brown solid with the yield of 94.59%, LC-MS:361.8,363.8[ M + 1% ] -LC-MS]+,tR1.572min (cis-trans isomer mixture).
Example 42: 1- (3-Hydroxycyclopentyl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridine-3- Radical) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
0.44g (1.21mmol) of intermediate 435,0.519g (1.82mmol) of compound 9A, 1.971g (6.05mmol) of cesium carbonate are suspended in 30ml of dioxane, 6ml of 2M sodium carbonate are added, and 0.099g (0.121mmol) of [1,1' -bis (diphenylphosphino) ferrocene are added under nitrogen protection]Palladium dichloride dichloromethane complex, nitrogen protection is carried out again, the temperature is increased to 110 ℃ for 5h, the reaction is finished, rotary evaporation concentration is carried out, 30ml of water is added, stirring is carried out, 30ml of dichloromethane is added, standing and liquid separation are carried out, 4 × 30ml of dichloromethane is used for extracting water phase, organic phases are combined, drying is carried out, and silica gel chromatography column (eluent: methanol: dichloromethane: 1:40) is carried out to obtain 183mg of solid a, 86mg of solid b, the total yield of 441[ M + 1] of LC-MS:441 is 50.46 percent]+,tR＝1.478min&1.416min (cis-trans isomer mixture).
(twenty) route twenty
An intermediate 441: 5-bromo-2- (1H-1,2, 4-triazol-1-yl) pyridine
4.11g (14.48mmol) of compound 440 and 1.2g (17.38mmol) of 1,2, 4-triazole are dissolved in 10ml of NMP, 4g (29mmol) of potassium carbonate are added and the mixture is stirred at 100 ℃ overnight. The reaction was cooled to room temperature, and 50ml of ice water was added to precipitate a solid. Filtering, washing with a little ice water, pumping to dry to obtain 3.257g of white solid crude product, and passing the crude product through a silica gel chromatographic column to obtain 1.7g of pure product. LC-MS 225,227[ M + 1]]+,tR＝1.851min.
Intermediate 442: 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2- (1H-1,2, 4-triazol-1-yl) pyridine
151mg (0.671mmol) of intermediate 441, 256mg (1.007mmol) of pinacol diboron diborate and 198mg of potassium acetate (2.01mmol) are suspended in 10ml of 1, 4-dioxane and, under nitrogen protection, 44mg (0.054mmol) of [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex are added and the reaction is stirred at T ═ 100 ℃ for 2 h. The reaction solution was used directly in the next reaction.
Intermediate 444: (S) -3- (3-methyl-8- (6- (1H-1,2, 4-triazol-1-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) pyrrolidine-1-carbamic acid tert-butyl ester
0.2g (0.447mmol) of intermediate 43b,0.183g (0.671mmol) of 442, 0.728g (2.235mmol) of cesium carbonate are suspended in 10ml of dioxane, 3ml of 2M sodium carbonate are added, and 0.037g (0.045mmol) of [1,1' -bis (diphenylphosphino) ferrocene are added under nitrogen protection]Palladium dichloride dichloromethane complex, nitrogen protection is carried out again, the temperature is increased to 110 ℃ for 5h, the reaction is finished, rotary evaporation concentration is carried out, 30ml of water is added, stirring is carried out, 30ml of dichloromethane is added, standing and liquid separation are carried out, the water phase is extracted by 30ml of × 3 dichloromethane, organic phases are combined, drying is carried out, and 161mg of brown solid is obtained after silica gel chromatography (eluent: methanol: dichloromethane 1:40) is carried out, the yield is 70.27%, LC-MS:512.9[ M + 1:40 ]]+,tR＝1.914min.
Intermediate 445: (S) -8- (6- (1H-1,2, 4-triazol-1-yl) pyridin-3-yl) -3-methyl-1- (pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
158mg (0.308mmol) of intermediate 444 are dissolved in 5ml of DCM, and the reaction is stirred for 1h with introduction of dry HCl gas under ice-water bath conditions. Vacuum-dried to obtain 127mg of gray solid with 100% yield.
Example 43: (S) -8- (6- (1H-1,2, 4-triazole-1-yl) pyridin-3-yl) -3-methyl-1- (1- (methylsulfonyl) Acyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
127mg (0.308mmol) of intermediate 445, 10ml of dichloromethane, 0.7ml of triethylamine, stirring for 10min to dissolve, 0.046ml of methyl benzenesulfonyl chloride, reacting overnight, 10ml of saturated sodium bicarbonate, separating, extracting the aqueous phase with 20ml of × 3 dichloromethane, combining the organic phases, drying with anhydrous sodium sulfate, and purifying by TLC plate to obtain 25mg of light yellow solid with the yield of 16.55%]+,tR＝1.570min.1H NMR(400MHz,DMSO)9.46(s,1H),9.08(s,1H),8.98(s,1H),8.61(d,J＝12.9Hz,2H),8.37(s,1H),8.22(d,J＝8.8Hz,1H),8.10(d,J＝8.8Hz,1H),8.00(d,J＝8.5Hz,1H),6.04–5.83(m,1H),3.94–3.83(m,2H),3.70(s,1H),3.55(s,3H),3.52–3.46(m,1H),3.06(s,3H),2.75–2.63(m,1H),2.47–2.38(m,1H).
Intermediate 712: 2- (1H-pyrazol-1-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine
Intermediate 711(150mg,0.67mmol) was dissolved in 10ml of 1, 4-dioxane, and under nitrogen protection, 253mg (1mmol) of pinacol diboron, 196mg (2.01mmol) of potassium acetate, and 40mg (0.05mmol) of [1, 1-bis (di-phenylphosphino) ferrocene ] palladium chloride were added, heated to 95 ℃ and reacted for 2h, cooled to room temperature, and the reaction solution was directly used for the next reaction.
Intermediate 713: (S) -3- (8- (6- (1H-pyrazol-1-yl) pyridin-3-yl) -3-methyl-2-carbonyl-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) tetrahydropyrrole-1-carboxylic acid tert-butyl ester
Intermediate 43b (200mg, 0.45mmol) was dissolved in 10ml of 1, 4-dioxane and under nitrogen protection, crude (0.67mmol) intermediate 712, 586mg (1.8mmol) of cesium carbonate, 4ml of 2mol/L sodium carbonate solution, 36mg (0.045mmol) [1, 1-bis (di-phenylphosphino) ferrocene]Heating the palladium chloride dichloromethane complex to 110 ℃, reacting for 5h, and cooling to room temperature. Dioxane was evaporated off, dissolved in 20ml saturated sodium bicarbonate solution and 20ml dichloromethane, the solution was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried and evaporated to dryness to give a crude product, which was chromatographed on silica gel column (eluent: methanol: dichloromethane ═ 1:10) to give 200mg of solid in 86.96% yield. LC-MS 511.9[ M + 1]]+,tR＝2.228min.
Intermediate 714: (S) -8- (6- (1H-pyrazol-1-yl) pyridin-3-yl) -3-methyl-1- (pyrrol-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
And dissolving the intermediate 713(200mg,0.39mmol) in 10ml dichloromethane, cooling to 0-10 ℃, introducing hydrogen chloride gas into the reaction system, reacting for 2h, and filtering to obtain a crude product which is directly used in the next step.
Example 44: (S) -8- (6- (1H-pyrazol-1-yl) pyridin-3-yl) -3-methyl-1- (1- (methylsulfonyl) pyrrole Alk-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
Intermediate 714 (crude) was dissolved in 10ml of dichloromethane, and 67mg (0.585mmol) of methanesulfonyl chloride and 158mg (1.56mmol) of triethylamine were added thereto, followed by stirring at room temperature overnight. Adding 30ml of saturated sodium bicarbonate solution, stirring for 30min, separating, extracting the water phase with dichloromethane, combining the organic phases, drying, evaporating to obtain a crude product, and performing silica gel column chromatography (eluent: methanol: dichloromethane: 1:10) on the crude product to obtain 53mg of the target compound of example 44 with the yield of 27.75%]+,tR＝1.801min.1HNMR(400MHz,DMSO)9.03(d,J＝2.3Hz,1H),8.99(s,1H),8.70(d,J＝2.5Hz,1H),8.61–8.51(m,2H),8.22(d,J＝8.9Hz,1H),8.14–8.02(m,2H),7.90(s,1H),6.69–6.62(m,1H),6.03–5.84(m,1H),3.97–3.82(m,2H),3.75–3.67(m,1H),3.56(s,3H),3.55–3.48(m,1H),3.07(s,3H),2.80–2.63(m,1H),2.49–2.29(m,1H).
An intermediate body 602: 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-1,2, 3-triazole
Compound 601(0.6g,3.69mmol) is dissolved in 15ml of 1, 4-dioxane, and under nitrogen protection, 1.125g (4.43mmol) of pinacol diboron, 1.086g (11.07mmol) of potassium acetate, 0.3g (0.37mmol) of [1, 1-bis (di-phenylphosphino) ferrocene ] palladium chloride dichloromethane complex are added, heated to 95 ℃ for 5h, and cooled to room temperature. 50ml of water was added, stirred for 30min and filtered to give 0.35g of a solid with a yield of 45.39%.
Intermediate 603: 5-bromo-2- (1-methyl-1H-1, 2, 3-triazol-4-yl) pyridine
Intermediate 602(0.1g,0.478mmol) was dissolved in 5ml of 1, 4-dioxane, and under nitrogen protection, 0.113g (0.399mmol) of 5-bromo-2-iodopyridine, 0.39g (1.197mmol) of cesium carbonate, 1ml of water, 0.057g (0.12mmol) of 2-dicyclohexylphosphonium-2 ',4',6' -triisopropylbiphenyl, 0.037g (0.04mmol) of tris (dibenzylideneacetone) dipalladium were added, heated to 110 ℃, reacted for 5h, and cooled to room temperature. Dioxane was evaporated off, dissolved in 20ml saturated sodium bicarbonate solution and 20ml dichloromethane, the solution was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried and evaporated to dryness to give a crude product, which was chromatographed on silica gel column (eluent: ethyl acetate: petroleum ether ═ 5:1) to give 0.05g of a solid with a yield of 43.48%. LC-MS 239,241[ M + 1]]+,tR＝3.351min.1H NMR(400MHz,DMSO)8.73(s,1H),8.60(s,1H),8.14(d,J＝8.5Hz,1H),7.98(d,J＝8.4Hz,1H),4.12(s,3H).
Intermediate 604: 2- (1-methyl-1H-1, 2, 3-triazol-4-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine
The intermediate 603(75mg,0.31mmol) is dissolved in 5ml of 1, 4-dioxane, 118mg (0.465mmol) of diboronate, 91mg (0.93mmol) of potassium acetate and 24mg (0.03mmol) of [1, 1-bis (di-phenylphosphino) ferrocene ] palladium chloride dichloromethane complex are added under the protection of nitrogen, the mixture is heated to 95 ℃ for reaction for 2.5h, the reaction solution is cooled to room temperature, and the reaction solution is directly used for the next reaction.
Intermediate 605: (S) -3- (3-methyl-8- (6- (1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) -2-carbonyl-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester
Intermediate 43b (115mg, 0.258mmol) was dissolved in 10ml of 1, 4-dioxane,under nitrogen protection, add crude (0.31mmol) intermediate 604, 336mg (1.032mmol) cesium carbonate, 2ml 2mol/L sodium carbonate solution, 21mg (0.026mmol) [1, 1-bis (diphenylphosphino) ferrocene]Heating the palladium chloride to 110 ℃, reacting for 5h, and cooling to room temperature. Dioxane was evaporated off, dissolved in 20ml saturated sodium bicarbonate solution and 20ml dichloromethane, the solution was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried and evaporated to dryness to give a crude product, which was chromatographed on silica gel column (eluent: methanol: dichloromethane ═ 1:10) to give 116mg of solid in 85.29% yield. LC-MS 526.9[ M + 1]]+,tR＝1.851min.
Intermediate 606: (S) -3-methyl-8- (6- (1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) -1- (pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
The intermediate 605(534mg, 1.014mmol) is dissolved in 10ml dichloromethane, cooled to 0-10 ℃, and hydrogen chloride gas is introduced into the reaction system for reaction for 2h, and 454mg solid is obtained by filtration with the yield of 100 percent and is directly used for the next reaction.
Example 45: (S) -3-methyl-8- (6- (1-methyl-1H-1, 2, 3-triazole-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
Intermediate 606 (crude) was dissolved in 20ml of dichloromethane, and 174mg (1.521mmol) of methanesulfonyl chloride, 410mg (4.056mmol) of triethylamine were added thereto, followed by stirring at room temperature for 3 hours. Adding 50ml saturated sodium bicarbonate solution, stirring for 30min, separating, extracting the water phase with dichloromethane, mixing the organic phases, drying, evaporating to obtain crude product, and subjecting the crude product to silica gel column chromatography (eluent:methanol dichloromethane ═ 1:30) to give 183mg of the title compound of example 45 in a yield of 35.67%. LC-MS 505.2[ M + 1]]+,tR＝1.510min.1H NMR(400MHz,DMSO)9.15(s,1H),8.98(s,1H),8.65(s,1H),8.59(s,1H),8.51–8.42(m,1H),8.19(dd,J＝17.1,8.5Hz,2H),8.10(d,J＝8.9Hz,1H),6.06–5.83(m,1H),4.16(s,3H),3.97–3.84(m,2H),3.76–3.65(m,1H),3.56(s,3H),3.54–3.48(m,1H),3.06(s,3H),2.77–2.66(m,1H),2.47–2.31(m,1H).
Intermediate 448: 5-bromo-2- (1H-1,2, 3-triazol-1-yl) pyridine
0.695g (17.38mmol) NaH is added to 20ml DMF, 1.2g (17.38mmol)1,2, 3-triazole are added in portions and stirred for 1h at room temperature, 4.11g (14.48mmol) compound 447 is added and dissolved with stirring, and the mixture is stirred overnight at 120 ℃ with increasing temperature T. The reaction was cooled to room temperature, and 50ml of ice water was added to precipitate a solid. Filtering, washing with a little ice water, draining to obtain 3.0g of white solid crude product, and passing 2g of the crude product through a silica gel chromatographic column to obtain 167mg of pure product. LC-MS 225,227[ M + 1]]+,tR＝1.728min.
Intermediate 449: 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2- (1H-1,2, 3-triazol-1-yl) pyridine
160mg (0.71mmol) of intermediate 448, 269mg (1.06mmol) of pinacol diboron and 209mg (2.13mmol) of potassium acetate are suspended in 10ml of 1, 4-dioxane and under nitrogen protection, 46mg (0.057mmol) of [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex are added and the reaction is stirred at 100 ℃ for 2 h. The reaction solution was used directly in the next reaction.
Intermediate 451 a: (S) -3- (3-methyl-8- (6- (1H-1,2,3 triazol-1-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) pyrrolidine-1-carbamic acid tert-butyl ester
0.15g (0.34mmol) of intermediate 43b,0.193g (0.71mmol) of intermediate 449, 0.554g (1.7mmol) of cesium carbonate, suspended in 10ml of dioxane, 2ml of 2M sodium carbonate and, under nitrogen, 0.028g (0.034mmol) of [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex, nitrogen protection again, heating to 110 ℃ for 5h, reaction is completed, rotary evaporation concentration is carried out, 25ml of water is added, stirring is carried out, 25ml of dichloromethane is added, standing and liquid separation are carried out, 25ml of × 3 dichloromethane is used for extracting water phase, organic phases are combined, drying and TLC plate preparation purification (developing solution: methanol: dichloromethane ═ 1:15) are carried out to obtain 0.15g of brown solid, yield is 86.07%, LC-MS:512.9[ M + 1:15 ] LC-MS: 86.07%]+,tR＝2.007min。
Intermediate 452 a: (S) -8- (6- (1H-1,2, 3-triazol-1-yl) pyridin-3-yl) -3-methyl-1- (pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
150mg (0.29mmol) of intermediate 451a are dissolved in 5ml DCM under ice-water bath and HCl gas is introduced and the reaction is stirred for 1 h. Vacuum-pumping to obtain gray solid 120mg, yield 100%.
Example 46: (S) -8- (6- (1H-1,2, 3-triazole-1-yl) pyridin-3-yl) -3-methyl-1- (1- (methylsulfonyl) amide Acyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
120mg (0.29mmol) of intermediate 452a, 8ml of dichloromethane and 0.6ml of triethylamine are added, the mixture is stirred for 10min to dissolve, 0.034ml of methyl benzenesulfonyl chloride is added, the reaction is carried out for 2h, 10ml of saturated sodium bicarbonate is added, liquid separation is carried out, the aqueous phase is extracted by 20ml of × 3 dichloromethane, the organic phases are combined, dried by anhydrous sodium sulfate and purified by TLC plate preparation (developing solution: methanol: dichloromethane ═ 1:10) to obtain 32mg of off-white powder, the yield is 22.49%. LC-MS:490.9[ M + 1:10 ]]+,tR＝1.603min.1H NMR(400MHz,DMSO)9.15(s,1H),8.99(s,1H),8.94(s,1H),8.71–8.58(m,2H),8.30–8.19(m,2H),8.12(d,J＝8.7Hz,1H),8.06(s,1H),6.08–5.81(m,1H),3.95–3.82(m,2H),3.75–3.67(m,1H),3.55(s,3H),3.53–3.45(m,1H),3.06(s,3H),2.77–2.64(m,1H),2.47–2.37(m,1H).
Intermediate 702: 1-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole
Compound 701(0.2g,1.24mmol) was dissolved in 5ml of 1, 4-dioxane, 0.378g (1.49mmol) of pinacol diboron, 0.365g (3.72mmol) of potassium acetate, and 0.11g (0.124mmol) of [1, 1-bis (di-phenylphosphino) ferrocene ] palladium chloride dichloromethane complex were added under nitrogen protection, heated to 95 ℃ for 5h, and cooled to room temperature. 15ml of water were added, stirred for 1 hour and filtered to give 0.114g of a solid with a yield of 44.19%.
Intermediate 703: 5-bromo-2- (1-methyl-1H-pyrazol-3-yl) pyridine
Intermediate 702(0.114g,0.548mmol) was dissolved in 5ml of 1, 4-dioxane, 0.130g (0.457mmol) of compound 105, 0.447g (1.371mmol) of cesium carbonate, 1ml of water, 0.027g (0.023mmol) of tetrakis (triphenylphosphine) palladium were added under nitrogen protection, heated to 110 ℃ and reacted for 5h,and cooling to room temperature. Dioxane was evaporated off, dissolved in 20ml saturated sodium bicarbonate solution and 20ml dichloromethane, the solution was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried and evaporated to dryness to give a crude product, which was chromatographed on silica gel column (eluent: ethyl acetate: petroleum ether ═ 3:1) to give 0.022g of solid with 20.18% yield. LC-MS:238,240[ M + 1]]+,tR＝1.866min.
Intermediate 704: 2- (1-methyl-1H-pyrazol-3-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine
The intermediate 703(88mg,0.37mmol) is dissolved in 5ml of 1, 4-dioxane, 141mg (0.465mmol) of pinacol diboron, 109mg (1.11mmol) of potassium acetate and 30mg (0.037mmol) of [1, 1-bis (di-phenylphosphino) ferrocene ] palladium chloride dichloromethane complex are added under the protection of nitrogen, the mixture is heated to 95 ℃, reacted for 2.5h, cooled to room temperature, and the reaction solution is directly used for the next reaction.
Intermediate 705: (S) -3- (3-methyl-8- (6- (1-methyl-1H-pyrazol-3-yl) pyridin-3-yl) -2-carbonyl-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester
Intermediate 43b (110mg, 0.247mmol) was dissolved in 10ml of 1, 4-dioxane, and under nitrogen protection, crude intermediate 704 (0.37mmol), 322mg (0.988mmol) cesium carbonate, 2ml water, 21mg (0.025mmol) of [1, 1-bis (diphenylphosphino) ferrocene]Heating the palladium chloride dichloromethane complex to 110 ℃, reacting for 5h, and cooling to room temperature. Evaporating dioxane, dissolving in 20ml saturated sodium bicarbonate solution and 20ml dichloromethane, separating, extracting water phase with dichloromethane, mixing organic phases, drying, evaporating to obtain crude product, and performing silica gel column chromatography (eluent: methanol: dichloromethane) on the crude product1:10) to yield 97mg of a solid with a yield of 74.62%. LC-MS 526.2[ M + 1]]+,tR＝1.923min.
Intermediate 706: (S) -3-methyl-8- (6- (1-methyl-1H-pyrazol-3-yl) pyridin-3-yl) -1- (pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
And dissolving the intermediate 705(97mg, 0.18mmol) in 5ml of dichloromethane, cooling to 0-10 ℃, introducing hydrogen chloride gas into the reaction system, reacting for 2 hours, and filtering to obtain a crude product which is directly used for the next reaction.
Example 47: (S) -3-methyl-8- (6- (1-methyl-1H-pyrazol-3-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) amide Yl) pyrrolidin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
Intermediate 706 (crude) was dissolved in 5ml of dichloromethane, and 31mg (0.27mmol) of methanesulfonyl chloride and 73mg (0.72mmol) of triethylamine were added thereto, followed by stirring at room temperature overnight. 20ml of saturated sodium bicarbonate solution was added, the mixture was stirred for 30min, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried and evaporated to dryness to obtain a crude product, which was subjected to silica gel column chromatography (eluent: methanol: dichloromethane ═ 1:10) to obtain 23mg of the target compound of example 47 in a yield of 25.38%. LC-MS 504.2[ M + 1]]+,tR＝1.539min.1H NMR(400MHz,DMSO)9.11(s,1H),8.97(s,1H),8.57(s,1H),8.37(d,J＝8.1Hz,1H),8.20(d,J＝8.8Hz,1H),8.06(dd,J＝17.2,8.3Hz,2H),7.82(s,1H),6.87(s,1H),6.00–5.87(m,1H),3.95(s,3H),3.93–3.82(m,2H),3.73–3.66(m,1H),3.55(s,3H),3.53–3.47(m,1H),3.06(s,3H),2.67(s,1H),2.46–2.39(m,1H).
Intermediate 471: 5-bromo-N' -methylpyridinimines hydrazide
Adding 0.788g (5.46mmol) of methylhydrazine sulfate into 20ml of ethanol, adding 1.42g (10.92mmol) of N, N-diisopropylethylamine in batches, stirring for 30min, adding 1g (5.46mmol) of compound 470, heating, refluxing, stirring overnight, adding 20ml of water for quenching, enabling the pH to be 2-3, extracting with 20ml of × 3 methyl tert-butyl ether, combining organic phases, drying, filtering, performing rotary evaporation concentration, performing vacuum pumping to obtain 0.279g of yellow solid, wherein the yield is 22.31%, LC-MS (liquid chromatography-mass spectrometry) 229,231[ M + 1% ], and LC-MS (liquid chromatography-mass spectrometry) is performed]+,tR＝0.604min.
Intermediate 472: 5-bromo-2- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridine
Under the condition of ice-water bath, 0.5g (2.18mmol) of intermediate 471 is added into 5ml (130.8mmol) of formic acid, the mixture is naturally heated to room temperature, the mixture is heated and refluxed for 2h in oil bath, 10ml of saturated sodium carbonate is added for quenching, 20ml of × 3DCM is added for extracting organic phases, the organic phases are combined, dried by a proper amount of anhydrous sodium sulfate, filtered and evaporated in a rotary manner and vacuum-dried to obtain a crude product, the crude product is passed through a silica gel chromatographic column (eluent: methanol: dichloromethane ═ 1:30) to obtain 101mg of brown solid, the yield is 19.38%, LC-MS:239,241[ M + 1] of the product is subjected]+,tR＝1.601min.
The intermediate 473: 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridine
100mg (0.42mmol) of intermediate 472, 160mg (0.63mmol) of diboronate and 124mg (1.26mmol) of potassium acetate are suspended in 5ml of 1, 4-dioxane under nitrogen protection, 38mg (0.046mmol) of [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex are added, and the reaction is stirred at T ═ 100 ℃ for 2 h. The reaction solution was used directly in the next reaction.
Intermediate 475: (S) -3- (3-methyl-8- (6- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) pyrrolidine-1-carbamic acid tert-butyl ester
0.125g (0.28mmol) of intermediate 43b,0.120g (0.42mmol) of intermediate 473, 0.456g (1.4mmol) of cesium carbonate are suspended in 5ml of dioxane, 1ml of 2M sodium carbonate are added, and 0.023g (0.028mmol) of [1,1' -bis (diphenylphosphino) ferrocene are added under nitrogen]Palladium dichloride dichloromethane complex, nitrogen protection again, reaction at 110 ℃ T for 5h, rotary evaporation concentration, addition of 20ml of water, stirring, addition of 20ml of dichloromethane, stirring, standing for liquid separation, extraction of the aqueous phase with 20ml of × 3 dichloromethane, combination of organic phases, drying, purification by TLC preparative plates (developing solution: methanol: dichloromethane 1:10) to obtain 0.056g of brown solid with yield 37.98% LC-MS:527[ M + 1:10 ]]+,tR＝1.726min.
Intermediate 476: (S) -8- (6- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-3-yl) -3-methyl-1- (pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
56mg (0.106mmol) of intermediate 475 were dissolved in 4ml of DCM under ice-water bath with HCl gas being passed through and the reaction stirred for 1 h. Vacuum-pumping to obtain gray solid 45mg, yield 100%.
Example 48: (S) -3-methyl-8- (6- (1-methyl-1H-1, 2, 4-triaza)Oxazol-3-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
45mg (0.106mmol) of intermediate 476, 5ml of dichloromethane and then 0.074ml of triethylamine were added, the mixture was stirred for 10min to dissolve, 0.013ml of methanesulfonyl chloride was added, the mixture was stirred overnight, 6ml of saturated aqueous sodium bicarbonate solution was added, liquid separation was performed, the aqueous phase was extracted with 6ml of × 4 dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and TLC preparative chromatography plate purification was performed (developing solution: methanol: dichloromethane ═ 1:15) to obtain 39mg of off-white powder, yield: 72.92%. LC-MS:505[ M + 1: [ M + 1% ], M-MS]+,tR＝1.478min.1HNMR(400MHz,DMSO)9.18(s,1H),8.97(s,1H),8.60(d,J＝10.8Hz,2H),8.45(dd,J＝8.3,2.1Hz,1H),8.19(dd,J＝15.0,8.5Hz,2H),8.11(d,J＝8.8Hz,1H),6.03–5.80(m,1H),3.99(s,3H),3.96–3.81(m,2H),3.74–3.66(m,1H),3.55(s,3H),3.54–3.47(m,1H),3.06(s,3H),2.76–2.63(m,1H),2.47–2.38(m,1H).
(twenty-one) route twenty-one
Intermediate 1502: (R) -3- ((6-chloro-3-nitro-1, 5-naphthyridin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester
3g (12.3mmol) of intermediate 1204 and 2.9g (14.7mmol) of the compound (R) -1-tert-butoxycarbonyl-3-aminopiperidine were dissolved in 20mL of N, N-dimethylformamide, and 3.7g (36.9mmol) of triethylamine was added thereto and the mixture was stirred at room temperature for 3 hours. TLC detection, after the reaction is finished, 100mL of water is added, and after stirring for 30 minutes, the mixture is filtered, washed and dried to obtain 4.3g of a product, namely a yellow solid, and the yield is 86%. TLC showed agreement with the racemic compound in route fifteen.
Intermediate 1503: (R) -3- ((3-amino-6-chloro-1, 5-naphthyridin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester
4.3g (10.5mmol) of intermediate 1502 were dissolved in 50mL of N, N-dimethylformamide under an ice-water bath. 11.9g (52.7mmol) of stannous dichloride dihydrate are added in portions over 30 minutes and stirred at room temperature for 3 hours. And (3) detecting by TLC (thin layer chromatography), after the reaction is finished, dropwise adding 10% sodium hydroxide aqueous solution into the reaction solution until the pH value is 8-9, filtering, extracting the filtrate by using dichloromethane, washing a filter cake by using dichloromethane, combining organic phases, washing by using water, washing by using brine, drying, and spin-drying to obtain 4.4g of a product, namely a reddish brown solid with the yield of 100%. TLC showed agreement with the racemic compound in route fifteen.
Intermediate 1504: (R) -3- (8-chloro-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] [1,5] naphthyridin-1-yl) piperidine-1-carboxylic acid tert-butyl ester
4.4g (10.5mmol) of intermediate 1503 was dissolved in 50mL of dichloromethane in an ice-water bath, 4.2g (42mmol) of triethylamine was added thereto, and the mixture was stirred for 10 minutes. A solution of 1.56g (5.25mmol) of triphosgene in 30mL of dichloromethane was added dropwise and stirred at 0 ℃ for 4 hours. And (3) detecting by TLC, after the reaction is finished, dropwise adding 100mL of saturated sodium bicarbonate solution into the reaction solution, quenching, stirring for 10 minutes, separating an organic phase, extracting an aqueous phase by using dichloromethane, combining the organic phases, drying, and spin-drying to obtain a crude product. The crude product was subjected to silica gel column chromatography (eluent: dichloromethane/methanol-40/1, V/V) to obtain 2.6g of the product as a yellowish solid in 61.9% yield. TLC showed agreement with the racemic compound in route fifteen.
Intermediate 1505: (R) -3- (8-bromo-3-methyl-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] [1,5] naphthyridin-1-yl) piperidine-1-carboxylic acid tert-butyl ester
2.6g (6.4mmol) of intermediate 1504 was dissolved in 50mL of dichloromethane, 0.2g (0.64mmol) of tetrabutylammonium bromide and 50mL of a 10% aqueous solution of sodium hydroxide were added, and the mixture was stirred for 10 minutes, then 2.7g (19.3mmol) of methyl iodide was added, and the mixture was stirred at room temperature overnight. And (3) TLC detection, standing for layering after the reaction is finished, separating out an organic phase, extracting an aqueous phase by using dichloromethane, combining the organic phases, drying and spin-drying to obtain a product 3.3g of a yellowish-brown solid with the yield of 100%. TLC showed agreement with the racemic compound in route fifteen.
An intermediate 1506: (R) -3- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] [1,5] naphthyridin-1-yl) piperidine-1-carboxylic acid tert-butyl ester
Under nitrogen, 1.8g (4.3mmol) of intermediate 1505 and 1.8g (6.45mmol) of intermediate 9A were dissolved in 50mL of dioxane, 7.0g (21.5mmol) of cesium carbonate, 10mL of 2M aqueous sodium carbonate solution and 0.35g (0.43mmol) of [1, 1-bis (diphenylphosphino) ferrocene ] palladium chloride were added, and the mixture was heated at 110 ℃ for 20 hours. And (3) TLC detection, after the reaction is finished, most of dioxane is rotated out, water is added, dichloromethane is used for extraction, organic phases are combined, and the mixture is dried and rotated to obtain a crude product. The crude product was subjected to silica gel column chromatography (dichloromethane/methanol-40/1, V: V) to obtain 1.6g of the product as a yellowish solid in 69.6% yield. TLC showed agreement with the racemic compound in route fifteen.
Intermediate 1507: (R) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (piperidin-3-yl) -1H-imidazo [4,5-c ] [1,5] naphthyridin-2 (3H) -one
Under an ice-water bath, 1.6g (2.9mmol) of intermediate 1506 was dissolved in 20mL of dichloromethane, and hydrogen chloride gas was introduced into the reaction solution for thirty minutes. TLC detection, after the reaction is finished, filtering, washing the solid with dichloromethane, and pumping out under reduced pressure to obtain 1.5g of a product which is earthy yellow solid with the yield of 100%. TLC showed agreement with the racemic compound in route fifteen.
Example 49: (R) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) amide Yl) piperidin-3-yl) -1H-imidazo [4,5-c][1,5]Naphthyridin-2 (3H) -ones
1.5g (2.9mmol) of intermediate 1507 was dissolved in 60mL of dichloromethane, 1.5g (14.5mmol) of triethylamine and 0.5g (4.4mmol) of methanesulfonyl chloride were added thereto, and the mixture was stirred at room temperature overnight. And (3) TLC detection, after the reaction is finished, adding 100mL of saturated sodium bicarbonate aqueous solution, stirring for 20 minutes, demixing, extracting the aqueous phase with dichloromethane, combining the organic phases, drying and spin-drying to obtain a crude product. The crude product was subjected to silica gel column chromatography (dichloromethane/methanol-10/1, V: V) to yield 1.0g of the product as a pale yellowish white solid in 66.7% yield. TLC showed agreement with the racemic compound in route fifteen. LC-MS 519.2[ M + 1]]+,tR＝1.728min.
(twenty-two) route twenty-two
Intermediate 615: (S) -3- (3-methyl-8- (6- (1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) -2-carbonyl-2, 3-dihydro-1H-imidazo [4,5-c ] [1,5] naphthyridin-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester
Intermediate 424(165mg, 0.408mmol) was dissolved in 10ml 1, 4-dioxane and under nitrogen protection, crude (0.49mmol) intermediate 604, 424mg (1.63mmol) cesium carbonate, 2ml 2mol/L sodium carbonate solution, 33mg (0.041mmol) [1, 1-bis (di-phenylphosphino) ferrocene ] was added]Heating the palladium chloride dichloromethane complex to 110 ℃, reacting for 5h, and cooling to room temperature. Dioxane was evaporated off, dissolved in 20ml saturated sodium bicarbonate solution and 20ml dichloromethane, the solution was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried and evaporated to dryness to give a crude product, which was chromatographed on silica gel column (eluent: methanol: dichloromethane ═ 1:10) to give 124mg of solid in 57.7% yield. LC-MS 528.3[ M + 1]]+,tR＝2.009min.
Intermediate 616: (S) -3-methyl-8- (6- (1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) -1- (pyrrolidin-3-yl) -1H-imidazo [4,5-c ] [1,5] naphthyridin-2 (3H) -one
And dissolving the intermediate 615(124mg, 0.235mmol) in 10ml of dichloromethane, cooling to 0-10 ℃, introducing hydrogen chloride gas into the reaction system, reacting for 2 hours, and filtering to obtain a crude product which is directly used for the next reaction.
Example 50: (S) -3-methyl-8- (6- (1-methyl-1H-1, 2, 3-triazole-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c][1,5]Naphthyridin-2 (3H) -ones
Intermediate 616 (crude) was dissolved in 10ml of dichloromethane, and 40mg (0.353mmol) of methanesulfonyl chloride and 95mg (0.94mmol) of triethylamine were added thereto and stirred at room temperature for 3 hours. Adding 30ml of saturated sodium bicarbonate solution, stirring for 30min, separating, extracting the water phase with dichloromethane, combining the organic phases, drying, evaporating to obtain a crude product, and performing silica gel column chromatography on the crude product (eluent: methanol: dichloromethane: 1:10) to obtain 32mg, wherein the yield is 26.89%. LC-MS 506.2[ M + 1]]+,tR＝1.664min.1HNMR(400MHz,DMSO)9.47(s,1H),9.11(s,1H),8.85(d,J＝8.6Hz,1H),8.68(s,1H),8.62(d,J＝8.9Hz,1H),8.50(d,J＝8.8Hz,1H),8.27(d,J＝8.1Hz,1H),6.58–6.45(m,1H),5.42–5.28(m,1H),4.17(s,3H),4.06–3.97(m,1H),3.59(s,3H),3.07(s,3H),3.03–2.87(m,1H),2.10–1.91(m,3H).
The following compounds were obtained according to scheme four.
Intermediate 604: 2- (1-methyl-1H-1, 2, 3-triazol-4-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine
76mg (0.32mmol) of intermediate 603, 122mg (0.48mmol) of pinacolatobisboronic acid pinacol ester and 94mg (0.96mmol) of potassium acetate are suspended in 6ml of 1, 4-dioxane under nitrogen protection, 26mg (0.032mmol) of [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex are added, and the reaction is stirred at 95 ℃ for 3 h. The reaction solution was used directly in the next reaction.
Example 51: 1- ((1s,4s) -4-hydroxycyclohexyl) -3-methyl-8- (6- (1-methyl-1H-1, 2, 3-triaza) Oxazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
100mg (0.266mmol) of intermediate 208,92mg (0.320mmol) of 604, 347mg (1.064mmol) of cesium carbonate are suspended in 6ml of 1, 4-dioxane, 2ml of 2M aqueous sodium carbonate solution are added, and 22mg (0.0266mmol) of [1,1' -bis (diphenylphosphino) ferrocene are added under nitrogen protection]Palladium dichloride dichloromethane complex, nitrogen protection again, heating to 110 ℃ for reaction for 5h, rotary evaporation and concentration, adding 20ml of water, stirring, adding 20ml of dichloromethane, stirring, standing for liquid separation, extracting an aqueous phase with 20ml of × 3 dichloromethane, combining organic phases, drying, and purifying by TLC silica gel preparation plate (eluent: methanol: dichloromethane ═ 1:10) to obtain 14mg of light yellow solid, yield: 11.6%. LC-MS:456[ M +1 ═ 10%]+,tR＝1.523min.1H NMR(400MHz,DMSO+D2O)9.33(s,1H),9.12(s,1H),8.68(s,1H),8.54–8.34(m,3H),8.25(d,J＝8.1Hz,1H),5.08–4.92(s,1H),4.16(s,3H),3.98(s,1H),3.60(s,3H),2.95–2.65(m,2H),2.04–1.61(m,6H).
The following compounds were obtained according to scheme ten.
Example 52: (R) -1- (1- (ethylsulfonyl) piperidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazole- 4-yl) pyridin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
Intermediate 55a (75mg,0.17mmol) was dissolved in 10ml of dichloromethane, and 33mg (0.26mmol) of ethylsulfonyl chloride and 69mg (0.68mmol) of triethylamine were added thereto and stirred at room temperature for 1.5 h. 15ml of saturated sodium bicarbonate solution was added, the mixture was stirred for 30min, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried and evaporated to dryness to obtain a crude product, which was subjected to silica gel column chromatography (eluent: methanol: dichloromethane ═ 1:10) to obtain 20mg of the target compound of example 52 in 22.09% yield. LC-MS 532[ M + 1]]+,tR＝3.384min.1H NMR(400MHz,DMSO)8.99(s,1H),8.92(s,1H),8.40(d,J＝13.9Hz,2H),8.21(dd,J＝21.4,7.4Hz,2H),8.12–7.97(m,2H),7.76(d,J＝8.3Hz,1H),5.10–4.98(m,1H),4.02(d,J＝10.5Hz,1H),3.91(s,3H),3.79–3.62(m,2H),3.51(s,3H),3.21–3.06(m,2H),2.96–2.68(m,J＝11.1Hz,2H),2.16(d,J＝12.1Hz,1H),1.96(d,J＝13.1Hz,1H),1.85–1.66(m,1H),1.19(t,J＝7.4Hz,3H).
Example 53: (R) -1- (1- (cyclopropylsulfonyl) piperidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyri-dine) Oxazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
Intermediate 55a (75mg,0.17mmol) was dissolved in 10ml of dichloromethane, and 37mg (0.26mmol) of cyclopropylsulfonyl chloride and 69mg (0.68mmol) of triethylamine were added and stirred at room temperature for 1.5 h. Adding 15ml of saturated sodium bicarbonate solution, stirring for 30min, separating, extracting the water phase with dichloromethane, combining the organic phases, drying, evaporating to obtain a crude product, and performing silica gel column chromatography on the crude product (eluent: methanol: dichloromethane ═ 1:10) to obtain 27mg of the target compound, wherein the yield is 29.16%. LC-MS 544[ M + 1]]+,tR＝3.459min.1HNMR(400MHz,DMSO)8.98(s,1H),8.92(s,1H),8.38(d,J＝5.6Hz,2H),8.27–8.13(m,2H),8.12–7.97(m,2H),7.76(d,J＝8.2Hz,1H),5.12–4.96(m,1H),4.04(d,J＝10.2Hz,1H),3.91(s,3H),3.80–3.61(m,2H),3.51(s,3H),2.91(t,J＝11.6Hz,1H),2.85–2.62(m,2H),2.16(d,J＝10.8Hz,1H),1.99(d,J＝14.1Hz,1H),1.87–1.69(m,1H),1.06–0.85(m,4H).
Example 54: (R) -3- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4, 5-c)]Quinolin-1-yl) piperidine-1-sulfonamides
100mg (0.195mmol) of intermediate 55a, 10ml dioxane, 136. mu.l triethylamine, stirring for 15min, 56mg sulfamide, refluxing at 100 ℃ overnight, removing the solvent by rotary evaporation, quenching with 20ml water, 20ml dichloromethane, stirring, standing for separating, extracting the aqueous phase with 3 × 20ml dichloromethane, combining the organic phases, drying, purifying on silica gel preparation plates (methanol: dichloromethane: 1:10) to obtain 12mg solid, yield: 11.87%, LC-MS:519[ M + 1:10 ] yield: 11.87%]+,tR＝3.226min.1HNMR(400MHz,DMSO)9.40(s,1H),9.07(s,1H),8.68–8.38(m,5H),8.27(s,1H),8.03(d,J＝7.8Hz,1H),6.98(s,2H),5.38–5.15(m,1H),3.94(s,3H),3.67–3.48(m,2H),3.57(s,3H),2.72–2.55(m,2H),2.27–2.13(m,1H),2.05–1.78(m,3H).
Example 55: (R) -N-ethyl-3- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2- Oxo-2, 3-dihydro-1H-imidazo [4,5-c]Quinolin-1-yl) piperidine-1-carboxamide
50mg (0.098mmol) of intermediate 55a, 5ml of dioxane, 28. mu.l of triethylamine, stirring for 30min, 9. mu.l of ethyl isocyanate, reflux reaction at 110 ℃ for 1h, rotary evaporation to remove the solvent, addition of 10ml of water for quenching, addition of 10ml of dichloromethane, stirring, standing for liquid separation, extraction of the aqueous phase with 3 × 10ml of dichloromethane, combination of the organic phases, drying, purification on silica gel plates (methanol: dichloromethane 1:10) to give 21mg of a solid, yield: 41.97%, LC-MS:511[ M + 1:10 ] as a solid]+,tR＝3.228min.1HNMR(400MHz,DMSO)9.42(s,1H),9.09(s,1H),8.88(s,1H),8.65(s,2H),8.59(d,J＝8.9Hz,1H),8.42(d,J＝8.7Hz,1H),8.33(s,1H),8.06(d,J＝8.0Hz,1H),6.79(s,1H),5.10–4.94(m,1H),4.47(d,J＝12.1Hz,1H),3.96(s,3H),3.58(s,3H),3.40(t,J＝11.9Hz,1H),3.15–3.00(m,2H),2.99–2.77(m,2H),2.16–1.43(m,4H),0.93(t,J＝7.0Hz,3H).
Example 56: (R) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- ((trifluoro-l) Methyl) sulfonyl) piperidin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
Dissolving 100mg (0.195mmol) of intermediate 55a in 10ml of dichloromethane, adding 136. mu.l of triethylamine, stirring for 10min, adding 40. mu.l of trifluoromethanesulfonic anhydride, making the system turn red, stirring at room temperature for 2h, adding 10ml of saturated sodium bicarbonate, quenching, stirring, standing for liquid separation, extracting the aqueous phase with 3 × 10ml of dichloromethane, combining the organic phases, drying, purifying with silica gel preparation plates (methanol: dichloromethane ═ 1:10) to obtain 50mg of red solid, yield: 44.86%, LC-MS:572[ M + 1:10 ]]+,tR＝3.884min.
(twenty-three) route twenty-three
Intermediate 458: (4-hydroxy-4-methylcyclohexyl) carbamic acid tert-butyl ester
2g (9.3mmol) of compound 400 are dissolved in 40ml of THF under nitrogen, cooled to-78 ℃ and 10ml of methylmagnesium bromide (3M) are added dropwise, after which they are allowed to warm to room temperature and are stirred overnight. Quenching with 200ml of saturated ammonium chloride aqueous solution, separating, extracting the aqueous phase with an equal volume of dichloromethane for 3 times, combining the organic phases, drying, filtering, evaporating to dryness to obtain 0.6g of yellow oily substance. LC-MS 174[ M +1-56 ]]+,tR＝1.759min.
Intermediate 459: 4-amino-1-methylcyclohexanol
0.6g of intermediate 458 was dissolved in 70ml of HCl/MeOH (10%), stirred at room temperature for 7h, the reaction was evaporated to dryness and taken up with 3X 20ml of dichloromethane to give 0.5g of a tan solid.
Intermediate 460: 4- ((6-bromo-3-nitroquinolin-4-yl) amino) -1-methylcyclohexanol
0.5g (2.6mmol) of intermediate 459 and 0.86g (8.5mmol) of triethylamine are added to 20ml of dichloromethane, stirred for 10min and then 0.5g (1.7mmol) of intermediate 3 are added, stirred at room temperature overnight, the reaction solution is evaporated to dryness and purified by a silica gel column, and two product dots are collected to obtain 170mg of a yellow solid (cis-trans isomer mixture). LC-MS 380,382[ M + 1]]+,tR＝2.036&2.107min.
Intermediate 461: 4- ((3-amino-6-bromo-4-yl) amino) -1-methylcyclohexanol
170mg (0.447mmol) of intermediate 460 are dissolved in 30ml of EtOH, 505mg (2.24mmol) of stannous chloride hydrate are added in portions, the mixture is stirred at room temperature overnight, the mixture is concentrated by rotary evaporation, 20ml of saturated sodium bicarbonate solution with 10% of sodium hydroxide solution is used for adjusting the pH value of the concentrate to be 8-9, 20ml of DCM is added for stirring, the mixture is kept stand, the phases are separated, the aqueous phase is extracted by 30ml of × 3DCM, the organic phases are combined and dried by anhydrous sodium sulfate, the mixture is evaporated to dryness to obtain 156mg of brown crystals (cis-trans-isomer mixture), the yield is 100%, LC-MS, 350,352[ M + 1] of the mixture is prepared]+,tR＝1.353&1.478min.
Intermediate 462: 8-bromo-1- (4-methyl-4-hydroxycyclohexyl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
156mg (0.447mmol) of the intermediate 461 is dissolved in 10ml of dichloromethane, 0.2ml (1.34mmol) of triethylamine is added under the condition of stirring in an ice-water bath, 67mg (0.224mmol) of triphosgene dissolved in 10ml of dichloromethane is added dropwise, the ice-water bath is stirred for 4h, 20ml of saturated sodium carbonate is added dropwise into the reaction solution, the mixture is stirred, the mixture is kept stand, liquid separation is carried out, the water phase is extracted by 20ml of × 4 dichloromethane, organic phases are combined, drying and solvent rotary drying are carried out to obtain a crude product, the crude product is subjected to silica gel chromatographic column (eluent: dichloromethane: 1:30) to obtain 29mg of brown solid (cis-trans-isomer mixture), the yield is 17.24%, LC-MS:376,378[ M +1]+,tR＝1.531&1.629min.
Intermediate 463: 8-bromo-3-methyl-1- (4-methyl-4-hydroxycyclohexyl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
29mg (0.077mmol) of intermediate 462 is dissolved in 2ml of dichloromethane, 3mg (0.0077mmol) of TBAB is added, 2ml of 10% NaOH is added and stirred for 10min, 14. mu.l (0.231mmol) of methyl iodide is added, stirring reaction is carried out at room temperature overnight, standing and liquid separation are carried out, the water phase is extracted by 3ml of × 6 dichloromethane, the organic phases are combined, dried, filtered, concentrated by rotary evaporation and vacuum pumping, 30mg of yellow solid (cis-trans-isomer mixture) is obtained, the yield is 100%, LC-MS 390,392[ M + 1] of]+,tR＝1.664&1.757min.
Example 57: 1- (4-hydroxy-4-methylcyclohexyl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyri-dine Pyridin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
30mg (0.077mmol) of intermediate 463,33mg (0.116mmol) of intermediate 9A, 126mg (0.385mmol) of cesium carbonate are suspended in 5ml of dioxane, 1ml of 2M sodium carbonate solution is added, and 7mg 0.0077mmol of [1,1' -bis (diphenylphosphino) ferrocene ] are added under nitrogen protection]Palladium dichloride dichloromethane complex, nitrogen protection again, heating to 110 ℃ for reaction for 5h, adding 2ml of water, stirring, adding 3ml of dichloromethane, stirring, standing for liquid separation, extracting an aqueous phase with 3ml of × 6 dichloromethane, combining organic phases, drying, purifying by silica gel TLC preparative plates (eluent: methanol: dichloromethane ═ 1:15) to obtain 18mg of brownish red solid (cis-trans isomer mixture), yield: 49.89%. LC-MS:469[ M + 1:15 ]]+,tR＝1.508&1.539min.
Twenty four routes
Intermediate 505: (R) -3- (3-methyl-8- (6- (1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) -2-carbonyl-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) piperidine-1-carboxylic acid tert-butyl ester
0.125g (0.27mmol) of intermediate 53a,0.093g (0.324mmol) of intermediate 604, 0.352g (1.08mmol) of cesium carbonate suspended in 5ml of dioxane, 2ml of 2M sodium carbonate added, 0.022g (0.027mmol) of [1,1' -bis (diphenylphosphino) ferrocene added under nitrogen protection]Palladium dichloride dichloromethane complex, protecting again with nitrogen, heating to 110 deg.C, reacting for 5h, removing solvent by rotary evaporation, adding 20ml water, 20ml dichloromethane, stirring, standing for liquid separation, and separating aqueous phase with 20ml × 3 dichloroMethane extraction, combined organic phases, dried and silica gel prep. plate purified (eluent: methanol: dichloromethane ═ 1:10) to yield 0.036g of a pale yellow solid, yield: 24.66 percent. LC-MS 541.2[ M + 1]]+,tR＝1.998min.
An intermediate 506: (R) -3-methyl-8- (6- (1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) -1- (piperidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
0.036g (0.067mmol) of intermediate 505 is dissolved in 5ml of dichloromethane, HCl gas is continuously introduced under the condition of ice water bath, and the reaction is stirred for 2 hours. After draining, 0.03g of solid was obtained, yield: 100 percent.
Example 58: (R) -3-methyl-8- (6- (1-methyl-1H-1, 2, 3-triazole-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) piperidin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
Suspending 30mg (0.067mmol) of intermediate 506 in 10ml of dichloromethane, adding 46. mu.l of triethylamine, stirring for 15min, dissolving the solid, adding 8. mu.l of methylsulfonyl chloride, stirring at room temperature overnight, adding 10ml of saturated sodium bicarbonate to quench, stirring, standing for liquid separation, extracting the aqueous phase with 3 × 10ml of dichloromethane, combining the organic phases, drying, purifying with silica gel preparation plates (methanol: dichloromethane ═ 1:10) to obtain 26mg of light yellow solid, yield: 75.28%. LC-MS:519[ M + 1:10 ]]+,tR＝1.465min.1HNMR(400MHz,DMSO+D2O)9.35(s,1H),9.14(s,1H),8.69(s,1H),8.62(s,1H),8.53–8.38(m,3H),8.19(d,J＝8.2Hz,1H),5.31–5.16(m,1H),4.16(s,3H),4.10(d,J＝10.1Hz,1H),3.82–3.68(m,2H),3.57(s,3H),3.53–3.48(m,1H),2.98(s,3H),2.91–2.67(m,2H),2.29–2.16(m,1H),2.07–1.93(m,1H),1.91–1.71(m,1H).
Twenty-five route
Intermediate 1701: 4- ((6-bromo-3-nitroquinolin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester
1.3g (4.5mmol) of Compound 3 and 1g (5mmol) of N-Boc-4-amino-piperidine were dissolved in 10mL of N, N-dimethylformamide, and 0.9g (9mmol) of triethylamine was added thereto and stirred at room temperature for 3 hours. TLC detection, after the reaction is finished, 60mL of water is added, the mixture is stirred for 20 minutes, then the mixture is filtered, and a filter cake is washed by water to obtain 1.1g of a product, yellow powder and the yield is 55.1%. LC-MS 451,453[ M + 1]]+,tR＝2.671min.
Intermediate 1702: 4- ((3-amino-6-bromoquinolin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester
Under an ice-water bath, 1.1g (2.4mmol) of intermediate 1701 was dissolved in 10mL of N, N-dimethylformamide. 2.7g (12.2mmol) of stannous dichloride dihydrate are added in portions over 30 minutes and stirred at room temperature for 2 hours. And (3) detecting by TLC (thin layer chromatography), after the reaction is finished, dropwise adding a 10% sodium hydroxide aqueous solution into the reaction solution until the pH value is 8-9, filtering, extracting the filtrate by using dichloromethane, washing a filter cake by using dichloromethane, combining organic phases, washing by using water, washing by using brine, drying, and spin-drying to obtain 1.1g of a product, namely a brown yellow solid with the yield of 100%. LC-MS 421,423[ M + 1]]+,tR＝1.981min.
Intermediate 1703: 4- (8-bromo-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) piperidine-1-carboxylic acid tert-butyl ester
Under an ice-water bath, 1.1g (2.4mmol) of intermediate 1702 was dissolved in 10mL of dichloromethane, 0.97g (9.6mmol) of triethylamine was added, and stirring was carried out for 10 minutes. A solution of 0.4g (1.44mmol) of triphosgene in 10mL of dichloromethane was added dropwise and stirred at 0 ℃ for 4 hours. And (3) detecting by TLC, after the reaction is finished, dropwise adding 20mL of saturated sodium bicarbonate solution into the reaction solution, quenching, stirring for 10 minutes, separating an organic phase, extracting an aqueous phase by using dichloromethane, combining the organic phases, drying and spin-drying to obtain a crude product. The crude product was subjected to silica gel column chromatography (eluent: dichloromethane/methanol-10/1, V/V) to obtain 0.6g of a product as an off-white solid in 55.8% yield. LC-MS 447,449[ M + 1]]+,tR＝2.199min.
Intermediate 1704: 4- (8-bromo-3-methyl-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) piperidine-1-carboxylic acid tert-butyl ester
0.6g (1.34mmol) of intermediate 1703 was dissolved in 30mL of dichloromethane, and 0.044g (0.134mmol) of tetrabutylammonium bromide and 30mL of 10% aqueous sodium hydroxide solution were added thereto, followed by stirring for 10 minutes, 0.57g (4mmol) of methyl iodide was added thereto, and the mixture was stirred for 4 hours. And (3) TLC detection, standing for layering after the reaction is finished, separating out an organic phase, extracting an aqueous phase by using dichloromethane, combining the organic phases, drying and spin-drying to obtain 0.6g of a product, namely a yellow solid with the yield of 100%. LC-MS 461,463[ M + 1]]+,tR＝2.364min.
Intermediate 1705: 4- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) piperidine-1-carboxylic acid tert-butyl ester
0.1g (0.22mmol) of intermediate 1704 and 0.092g (0.32mmol) of intermediate 9A were dissolved in 10mL of dioxane under nitrogen atmosphere, 0.358g (7.5mmol) of cesium carbonate and 2mL of 2M aqueous sodium carbonate solution were added, 0.025g (0.022mmol) of tetrakis (triphenylphosphine) palladium was added, and the mixture was heated at 110 ℃ for 5 hours. And (3) TLC detection, after the reaction is finished, most of dioxane is rotated out, water is added, dichloromethane is used for extraction, organic phases are combined, and the mixture is dried and rotated to obtain a crude product. The crude product was subjected to silica gel column chromatography (dichloromethane/methanol-20/1, V: V) to obtain 0.02g of the product as a white solid in 16.8% yield. LC-MS 484[ M-56+ 1]]+,tR＝3.995min.
Intermediate 1706: 3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (piperidin-4-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
0.02g (0.037mmol) of intermediate 1705 was dissolved in 5mL of dichloromethane in an ice-water bath, and hydrogen chloride gas was introduced into the reaction solution for thirty minutes. TLC detection, after the reaction is finished, filtration is carried out, the solid is washed by dichloromethane and is dried by suction under reduced pressure, and 0.02g of a product is obtained, and the yield is 100 percent.
Example 59: 3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) Piperidin-4-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
0.02g (0.037mmol) of intermediate 1706 is dissolved in 5mL of methylene chloride, and 0.018g (0.185mmol) is addedTriethylamine was added to the reaction solution, and 0.006g (0.056mmol) of methanesulfonyl chloride was added thereto, and the mixture was stirred at room temperature overnight. And (3) TLC detection, after the reaction is finished, adding 10mL of saturated sodium bicarbonate aqueous solution, stirring for 20 minutes, demixing, extracting the aqueous phase by using dichloromethane, combining the organic phases, drying and spin-drying to obtain a crude product. The crude product was subjected to silica gel column chromatography (dichloromethane/methanol-10/1, V: V) to obtain 0.01g of the product as a white solid in 52.3% yield. LC-MS 518[ M + 1]]+,tR＝3.245min.
(twenty-six) route twenty-six
Intermediate 1801: 4- (3-methyl-8- (6- (1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) piperidine-1-carboxylic acid tert-butyl ester
0.25g (0.54mmol) of intermediate 1704 and 0.186g (0.65mmol) of intermediate 604 are dissolved in 5mL of dioxane under nitrogen, 0.527g (1.62mmol) of cesium carbonate, 3mL of 2M aqueous sodium carbonate solution and 0.044g (0.054mmol) of [1, 1-bis (diphenylphosphino) ferrocene]Palladium chloride was heated at 110 ℃ for 5 hours. And (3) TLC detection, after the reaction is finished, most of dioxane is rotated out, water is added, dichloromethane is used for extraction, organic phases are combined, and the mixture is dried and rotated to obtain a crude product. The crude product was subjected to silica gel column chromatography (dichloromethane/methanol-20/1, V: V) to obtain 0.16g of the product as a yellowish solid in 54.9% yield. LC-MS 541.3[ M + 1]]+,tR＝1.964min.
Intermediate 1802: 3-methyl-8- (6- (1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) -1- (piperidin-4-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
Under an ice-water bath, 0.16g (0.29mmol) of intermediate 1801 was dissolved in 8mL of dichloromethane, and hydrogen chloride gas was introduced into the reaction solution for thirty minutes. TLC detection, after the reaction is finished, filtration is carried out, the solid is washed by dichloromethane and is dried by suction under reduced pressure, and 0.12g of a product is obtained, and the yield is 74.5 percent.
Example 60: 3-methyl-8- (6- (1-methyl-1H-1, 2, 3-triazole-4-yl) pyridine-3-yl) -1- (1- (methyl) Sulfonyl) piperidin-4-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
0.06g (0.12mmol) of intermediate 1802 was dissolved in 5mL of dichloromethane, 0.06g (0.18mmol) of triethylamine was added, and 0.02g (0.18mmol) of methanesulfonyl chloride was further added, and the mixture was stirred at room temperature overnight. And (3) TLC detection, after the reaction is finished, adding 10mL of saturated sodium bicarbonate aqueous solution, stirring for 20 minutes, demixing, extracting the aqueous phase by using dichloromethane, combining the organic phases, drying and spin-drying to obtain a crude product. The crude product was subjected to silica gel column chromatography (dichloromethane/methanol-10/1, V: V) to obtain 0.02g of the product as a white solid in 31.7% yield. LC-MS 519.2[ M + 1]]+,tR＝1.648min.1H NMR(400MHz,DMSO)9.13(s,1H),8.95(s,1H),8.65(s,1H),8.55(s,1H),8.39(d,J＝6.1Hz,1H),8.21(dd,J＝8.5,2.9Hz,2H),8.09(d,J＝8.3Hz,1H),5.14–5.00(m,1H),4.15(s,3H),3.81(d,J＝9.0Hz,2H),3.53(s,3H),3.08(t,J＝11.4Hz,2H),2.99(s,3H),2.84–2.63(m,3H),2.12(d,J＝11.7Hz,2H).
(twenty seven) route twenty seven
Intermediate 491: 3- ((6-bromo-3-nitroquinolin-4-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester
0.316g (1.10mmol) of Compound 3 and 0.3g (1.33mmol) of 3-amino-8-azabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (endo configuration) was dissolved in 10ml of dichloromethane, 0.31ml (2.20mmol) of triethylamine was added thereto, and the mixture was stirred at room temperature for 5 hours to precipitate a solid. Filtering, washing with a small amount of dichloromethane, and draining; the filtrate was chromatographed on silica gel (PE: EA 2:1 to EA) to give 0.419g of a yellow solid in a yield of 79.80%. LC-MS 477,479[ M + 1]]+,tR＝2.820min.
Intermediate 492: 3- ((6-bromo-3-aminoquinolin-4-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester
Dissolving 0.419g (0.878mmol) of intermediate 491 in 10ml DMF, adding 0.99g (4.39mmol) of stannous chloride hydrate in batches, stirring for 2h at room temperature, adjusting pH to 8-9 with 10% sodium hydroxide solution, quenching, adding 100ml of water and 100ml of dichloromethane, stirring, standing, separating phases, extracting the water phase with 3 × 80ml of dichloromethane, combining the organic phases, drying with anhydrous sodium sulfate, evaporating to dryness to obtain brown solid 0.392g, and obtaining the yield of 100% LC-MS (liquid chromatography-Mass Spectrometry): 447,449[ M + 1: (LC-MS): 447,449[ (. M + 1)]+,tR＝2.103min.
Intermediate 493: 3- (8-bromo-2-carbonyl-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester
0.392g (0.878mmol) of intermediate 492 are dissolved in 10ml of dichloro-chlorideAdding 0.37ml (2.634mmol) of triethylamine dropwise into methane under the condition of stirring in an ice-water bath, adding 0.131g (0.439mmol) of triphosgene dissolved in 7ml of dichloromethane, stirring in an ice-water bath for 5.5h, adding 20ml of saturated sodium bicarbonate dropwise into the reaction solution, quenching, stirring, standing, separating, extracting the aqueous phase with 3 × ml of dichloromethane, combining the organic phases, drying, and spin-drying to obtain a crude product, passing the crude product through a silica gel chromatographic column (eluent: methanol: dichloromethane ═ 1:20) to obtain 0.129g of brown solid, wherein the yield is 31.04%]+,tR＝2.382min.
Intermediate 494: 3- (8-bromo-2-carbonyl-3-methyl-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester
Dissolving 0.129g (0.27mmol) of intermediate 493 in 5ml of dichloromethane, adding 0.009g (0.027mmol) of TBAB, adding 5ml of 10% NaOH, stirring for 10min, adding 0.051ml (0.82mmol) of methyl iodide, stirring at room temperature for reaction overnight (20h), standing the reaction solution, separating, extracting the aqueous phase with 3 × 5ml of dichloromethane, combining the organic phases, drying, rotary steaming for concentration, and draining to obtain 0.131g of brownish red solid, wherein the yield is 100% LC-MS (liquid chromatography-Mass Spectrometry): 487,489[ M + 1] (M-1)]+,tR＝2.632min.
Intermediate 495: 3- (8- (6- (1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester
0.131g (0.27mmol) of intermediate 494,0.093g (0.324mmol) of intermediate 604, 0.352g (1.08mmol) of cesium carbonate, suspended in 8ml of dioxane, 2ml of 2M sodium carbonate was added, and 0.038g (0.048mmol) of [1,1' -bis (diphenylphosphino) ferrocene was added under nitrogen protection]Palladium dichloride dichloromethane complexUnder nitrogen protection, heating to 110 deg.C for 5h, adding 20ml water, stirring, adding 20ml dichloromethane, stirring, standing, separating, extracting water phase with 20ml × 3 dichloromethane, mixing organic phases, drying, and passing through silica gel plate (eluent: methanol: dichloromethane: 1:10) to obtain brown solid 0.032g with yield of 22.88%]+,tR＝2.048min.
Intermediate 496: 1- (8-azabicyclo [3.2.1] octan-3-yl) -3-methyl-8- (6- (1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
0.032g (0.056mmol) of intermediate 495 was dissolved in 3ml of dichloromethane, HCl gas was continuously introduced under the condition of ice-water bath, and the reaction was stirred for 1 hour. Pumping to dry to obtain solid 0.026g, yield: 100 percent.
Example 61: 3-methyl-8- (6- (1-methyl-1H-1, 2, 3-triazole-4-yl) pyridine-3-yl) -1- (8- (methyl) Sulfonyl) -8-azabicyclo [3.2.1]Octane-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
26mg (0.056mmol) of the intermediate 496, 5ml of dichloromethane, 78. mu.l of triethylamine, stirring for 15min, dissolving the solid, 14. mu.l of methylsulfonyl chloride, reacting overnight, 6ml of saturated sodium bicarbonate, quenching, stirring, standing for liquid separation, extracting the aqueous phase with 3 × 6ml of dichloromethane, combining the organic phases, drying, purifying with silica gel preparation plates (methanol: dichloromethane ═ 1:10) to obtain 30mg of off-white solid with a yield of 100%. LC-MS:545[ M + 1: (M-1): 100% >]+,tR＝1.728min.
(twenty-eight) route twenty-eight
Intermediate 509: 3- (8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -3-methyl-2-carbonyl-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester
0.050g (0.103mmol) of intermediate 494,0.044g (0.155mmol) of 9A, 0.168g (0.515mmol) of cesium carbonate are suspended in 6ml of dioxane, 1ml of 2M sodium carbonate is added, and 0.009g (0.0103mmol) of [1,1' -bis (diphenylphosphino) ferrocene is added under nitrogen protection]Palladium dichloride dichloromethane complex, protecting with nitrogen again, heating to T110 ℃ for 5h, removing solvent by rotary evaporation, adding 10ml of water, 10ml of dichloromethane, stirring, standing for liquid separation, extracting aqueous phase with 10ml of × 3 dichloromethane, combining organic phases, drying, purifying with silica gel preparation plate (eluent: methanol: dichloromethane 1:10) to obtain 0.019g of solid, yield: 32.61%, LC-MS:565.9[ M + 1:10 ]]+,tR＝2.853min.
An intermediate body 510: 1- (8-azabicyclo [3.2.1] octan-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
0.019g (0.034mmol) of intermediate 509 was dissolved in 5ml of dichloromethane, and HCl gas was continuously introduced into the solution under the ice-water bath condition, followed by stirring and reacting for 2 hours. After draining, 0.015g of solid was obtained, yield: 100 percent.
Example 62: 3-methyl-8- (6- (1-methyl-1H-pyrazine)Oxazol-4-yl) pyridin-3-yl) -1- (8- (methylsulfonyl) - 8-azabicyclo [3.2.1]Octane-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
16mg (0.034mmol) of intermediate 510, 5ml of dichloromethane, 24. mu.l of triethylamine, stirring for 10min, dissolving the solid, adding 5 drops of methanesulfonyl chloride, stirring for reaction for 3h at room temperature, adding 5ml of saturated sodium bicarbonate, quenching, stirring, standing for liquid separation, extracting the aqueous phase with 3 × 5ml of dichloromethane, combining the organic phases, drying, purifying with silica gel preparation plates (methanol: dichloromethane ═ 1:10) to obtain 18mg of off-white solid with a yield of 100%. LC-MS:544[ M + 1:10 ]]+,tR＝3.353min.
(twenty-nine) route twenty-nine
Intermediate 701 a: 2- ((6-bromo-3-nitroquinolin-4-yl) amino) ethylcarbamic acid tert-butyl ester
Intermediate 700a (0.836g,5.22mmol) was dissolved in 10ml of dichloromethane, 1.06g (10.44mmol) of triethylamine and 1g (3.48mmol) of intermediate 3 were added, stirred at room temperature for 3h, filtered and dried to give 1.007g of a yellow solid with a yield of 70.37%.
Intermediate 702 a: 2- ((3-amino-6-bromoquinolin-4-yl) amino) ethylcarbamic acid tert-butyl ester
Intermediate 701a (580mg, 1.41mmol) was dissolved in 5ml of N, N-dimethylformamide, and 1.591g (7.05mmol) of water and stannous chloride were added in portions and stirred at room temperature for 3 h. The reaction mixture was slowly poured into 50ml of saturated sodium bicarbonate solution and 50ml of dichloromethane, the liquid was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed with an equal amount of saturated brine, the organic phase was dried and evaporated to dryness to obtain 1.627g of a reddish brown liquid. LC-MS 381,383[ M + 1]]+,tR＝3.366min.
Intermediate 703 a: 2- (8-bromo-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) ethylcarbamic acid tert-butyl ester
Intermediate 702a (1.627g, crede) was dissolved in 5ml of dichloromethane, 0.57g (5.64mmol) of triethylamine was added, and a solution of 0.209g (0.705mmol) of triphosgene in 5ml of dichloromethane was added dropwise under ice-bath cooling, and the reaction was maintained at 0 ℃ for 3 hours after the addition. 20ml of saturated sodium bicarbonate solution is added dropwise, liquid separation is carried out, the water phase is extracted by dichloromethane, organic phases are combined, drying and evaporation are carried out to obtain a crude product, and the crude product is subjected to silica gel column chromatography (eluent: methanol: dichloromethane ═ 1:10) to obtain 0.14g of yellow solid with the yield of 24.39%. LC-MS 407,409[ M + 1]]+,tR＝4.163min.
Intermediate 704 a: 2- (8-bromo-3-methyl-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) ethylcarbamic acid tert-butyl ester
The intermediate 703a (0.14g,0.34mmol) was dissolved in 5ml of dichloromethane, 0.011g (0.034mmol) of tetra-n-butylammonium bromide, 5ml of 10% sodium hydroxide solution, 0.145g (1.02mmol) of methyl iodide were added, stirred at room temperature overnight, the liquid was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried and evaporated to dryness to give 0.17g of a yellow solid.
Intermediate 705 a: 2- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) ethylcarbamic acid tert-butyl ester
Intermediate 704a (0.17g, crede) was dissolved in 5ml of 1, 4-dioxane, and 0.145g (0.51mmol) of intermediate 9A, 0.332g (1.02mmol) of cesium carbonate, 1ml of 2mol/L sodium carbonate solution, 0.028g (0.034mmol) of [1, 1-bis (di-phenylphosphino) ferrocene]Heating the palladium chloride dichloromethane complex to 110 ℃, reacting for 5h, and cooling to room temperature. Dioxane was evaporated off, dissolved in 10ml saturated sodium bicarbonate solution and 10ml dichloromethane, the solution was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried and evaporated to dryness to give a crude product, which was chromatographed on silica gel column (eluent: methanol: dichloromethane ═ 1:30) to give 0.07g of a solid with a yield of 41.18%. LC-MS 500.2[ M + 1] ]+,tR＝2.205min.
Intermediate 706 a: 1- (2-aminoethyl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one s
Intermediate 705a (0.07g, 0.14mmol) was dissolved in 3ml of dichloromethane, 1ml of 14.4% methanol hydrochloride solution was added, stirred overnight at room temperature, and filtered to give 51mg of a solid with a yield of 91.07%.
Example 63: n- (2- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4, 5-c)]Quinolin-1-yl) ethyl) methanesulfonamide
Intermediate 706a (40mg,0.1mmol) was dissolved in 3ml dichloromethane, 17mg (0.15mmol) methanesulfonyl chloride, 40mg (0.4mmol) triethylamine were added and stirred at room temperature for 3 h. Adding 10ml of saturated sodium bicarbonate solution, stirring for 30min, separating, extracting the water phase with dichloromethane, combining the organic phases, drying, evaporating to obtain a crude product, and performing silica gel column chromatography on the crude product (eluent: methanol: dichloromethane ═ 1:10) to obtain 20mg of a target compound, wherein the yield is 41.88%. LC-MS 478.2[ M +1 ]]+,tR＝1.565min.1HNMR(400MHz,DMSO)9.05(d,J＝1.9Hz,2H),8.54(s,1H),8.39(s,1H),8.31(dd,J＝8.3,2.3Hz,1H),8.22(d,J＝9.1Hz,1H),8.16–8.11(m,1H),8.10(s,1H),7.80(d,J＝8.2Hz,1H),7.44(t,J＝6.3Hz,1H),4.58(t,J＝6.6Hz,2H),3.92(s,3H),3.58(s,3H),3.13-3.04(m,2H),2.89(s,3H).
(thirty) route thirty
Intermediate 513: 3- ((6-bromo-3-nitroquinolin-4-yl) amino) azetidine-1-carboxylic acid tert-butyl ester
0.279g (0.97mmol) of Compound 3 and 0.217g (1.26mmol) of tert-butyl 3-aminoazetidine-1-carboxylate in 15ml of dichloromethane are added 0.27ml (1.94mmol) of triethylamine, stirred at room temperature overnight, 30ml of water are added, the mixture is left to stand, the phases are separated, the aqueous phase is extracted with 3 × 20ml of dichloromethane, the organic phases are combined, dried over anhydrous sodium sulfate, filtered, rotary evaporated and dried to obtain 0.374g of a brown solid, the yield is 91.09%. LC-MS:423,425[ M + 1%]+,tR＝7.008min.
Intermediate 514: 3- ((6-bromo-3-aminoquinolin-4-yl) amino) azetidine-1-carboxylic acid tert-butyl ester
Dissolving 0.370g (0.87mmol) of intermediate 513 in 10ml of DMF, adding 0.986g (4.37mmol) of stannous chloride hydrate in batches, stirring overnight at room temperature, adjusting the pH to 8-9 by using 10% sodium hydroxide solution, adding 80ml of water and 20ml of dichloromethane, stirring, standing, separating phases, extracting the aqueous phase by using 3 × 20ml of dichloromethane, combining the organic phases, backwashing by using 80ml of saturated saline solution, drying the organic phase by using anhydrous sodium sulfate, filtering, performing rotary evaporation, performing suction drying, and passing the crude product through a silica gel chromatographic column (eluent: ethyl acetate: petroleum ether: 3:1) to obtain 0.106g of oily substance with the yield of 30.98%, and performing LC-MS:393,395[ M +1 ═ 3:1 ]]+,tR＝3.571min.
Intermediate 515: 3- (8-bromo-2-carbonyl-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) azetidine-1-carboxylic acid tert-butyl ester
Dissolving 0.106g (0.27mmol) of intermediate 514 in 5ml of dichloromethane, dropwise adding 0.113ml (0.81mmol) of triethylamine under the condition of stirring in an ice-water bath, adding 0.040g (0.135mmol) of triphosgene dissolved in 5ml of dichloromethane, stirring in an ice-water bath for 2.5h, dropwise adding 10ml of saturated sodium bicarbonate into the reaction solution, quenching, stirring, standing, separating liquid, extracting the aqueous phase with 3 × ml of dichloromethane, combining organic phases, drying, and spin-drying to obtain a crude product, passing the crude product through a silica gel chromatographic column (eluent: methanol: dichloromethane: 1:20) to obtain 0.046g of brown solid, wherein the yield is 40.64%]+,tR＝4.477min.
Intermediate 516: 3- (8-bromo-3-methyl-2-carbonyl-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) azetidine-1-carboxylic acid tert-butyl ester
Dissolving 0.044g (0.105mmol) of intermediate 515 in 5ml of dichloromethane, adding 0.004g (0.0105mmol) of TBAB, adding 5ml of 10% NaOH, stirring for 10min, adding 0.020ml (0.315mmol) of methyl iodide, stirring at room temperature, reacting for 3h, standing the reaction solution, separating liquid, extracting an aqueous phase with 3 × 5ml of dichloromethane, combining organic phases, drying, carrying out rotary evaporation, and carrying out suction drying to obtain 0.045g of yellow solid, wherein the yield is 100%. LC-MS (liquid chromatography-mass spectrometry) is represented by 433,435[ M + 1% ]]+,tR＝3.353min.
An intermediate 517: 3- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-carbonyl-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) azetidine-1-carboxylic acid tert-butyl ester
0.045g (0.105mmol) of intermediate 516, 0.045g (0.158mmol) of 9A, 0.171g (0.525mmol) of cesium carbonate are suspended in 6ml of dioxane, 12ml of 2M sodium carbonate are added, and 0.009g (0.0105mmol) of [1,1' -bis (diphenylphosphino) ferrocene are added under nitrogen protection]Palladium dichloride dichloromethane complex, nitrogen protection again, heating to 110 ℃ T for reaction for 5h, rotary evaporation to remove solvent, adding 10ml of water and 10ml of dichloromethane, stirring, standing for liquid separation, extracting an aqueous phase with 10ml of × 2 dichloromethane, combining organic phases, drying, passing through a silica gel preparation plate (eluent: methanol: dichloromethane 1:10) to obtain 0.043g of brown solid, the yield: 80.05%, LC-MS:512[ M + 1:10 ]]+,tR＝3.757min.
Intermediate 518: 1- (azetidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
0.043g (0.084mmol) of intermediate 517 is dissolved in 5ml of dichloromethane, HCl gas is continuously introduced under the condition of ice-water bath, and the reaction is stirred for 2 hours. Suction dried to obtain solid 0.035g, yield: 100 percent.
Example 64: 3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) Azetidin-3-yl) -1H-imidazo [4,5-c]Quinolin-2 (3H) -ones
35mg (0.084mmol) of intermediate 518, 5ml of dichloromethane and 59. mu.l of triethylamine were added, stirring was carried out for 15min, the solid was dissolved, 10. mu.l of methanesulfonyl chloride was added, the reaction was carried out overnight, 10ml of saturated sodium bicarbonate was added to quench, stirring was carried out, liquid separation was carried out by standing, the aqueous phase was extracted with 3 × 10ml of dichloromethane, the organic phases were combined, drying was carried out, and a silica gel preparation plate (methanol: dichloromethane ═ 1:10) was used to obtain 16mg of pale yellow solid powder with a yield of 38.91%. LC-MS:490[ M + 1: (M]+,tR＝1.925min.
Biological Activity assay
The compounds of the invention were tested for biological activity as follows:
mTOR kinase activity assay: inhibition of mTOR protein kinase activity by compounds is determined using an in vitro enzyme activity assay. The detection kit provided by Invitrogen was used to detect the inhibition of mTOR protease activity. The test principle is as follows: the mTOR kinase, fluorescein-labeled substrate and ATP were mixed and after reaction, EDTA and terbium-labeled primary antibody were added. The "time-resolved fluorescence resonance energy transfer" (TR-FRET) effect is enhanced after the antibody recognizes a substrate that is phosphorylated and labeled with fluorescein during mTOR kinase chemistry. The TR-FRET effect is calculated by the ratio of the acceptor fluorescein signal to the donor terbium signal. The amount of antibody bound to the tracer is directly proportional to the amount of phosphorylated substrate after the reaction, in this way the kinase activity can be detected. In this assay, the substrate for mTOR kinase is 4E binding protein 1(GFP-4EBP1) linked to green fluorescent protein.
1.1 materials and instruments:
4-hydroxyethylpiperazineethanesulfonic acid (HEPES, Sigma, Cat # SH3375), ethyleneglycol-bis- (2-aminoethylether) tetraacetic acid (EGTA, Sigma, Cat # E3889), manganese chloride (MnCl2, Sigma, Cat # M1787), Tween-20 (Tween-20, Amresco), 1,4 dithiothreitol (DTT, Merck, CB233155),
adenosine triphosphate (ATP, sigma, a7699), mammalian target of rapamycin (mTOR, Invitrogen, Cat # PV4753), antibodies against threonine 46 phosphorylated 4E binding protein 1 (lantha screenTMTb-anti-p4E-BP1(pThr46) Antibody, Invitrogen, Cat # PV4757), Green fluorescent protein-linked 4E binding protein 1(GFP-4E-BP1, Invitrogen, Cat # PV4759), TR-FRET diluent (TR-FRET Dilution Buffer, Invitrogen, Cat # PV3574), Proxi plates, Black (ProxiPlate, Black, PerkinElmer, detection plates), 384 well plates (384-well plates, Corning, Dilution plates), Nunc PP plates (Nunc PP plate, Corning, Dilution plates), Envision-2104 plate reader (Perkin Elmer).
1.2 solution and reagent preparation:
1.2.11 buffer storage solution for detection: 50mM HEPES pH7.5,1mM EGTA, 0.01% Tween-20,10mM MnCl2,mM DTT。
1.2.2 substrate working solution: 4mL of 2.5 Xsubstrate (1000 reactions) 3.8mL of 1 Xdetection solution, 191. mu.L of LGFP-4E-BP1 (20.96. mu.M stock solution), 10. mu.L of ATP (10 mM). Final concentration 0.4. mu.M GFP-4E-BP 1; 10M ATP.
1.2.3 mTOR working solution: 4mL of 2.5 XmTOR (1000 reactions): 4 mL.
1.2.41 × detection solution; 7.5 μ L mTOR (0.4mg/mL stock), final concentration 0.3 μ g/mL.
1.2.5 detection of working solution: 10mL of 2 × assay buffer (1000 reactions), 9.6mL of TR-FRET diluent, 11.5. mu.L of Tb-anti-p4E-BP1 antibody (stock 3.49. mu.M), 400. mu.L of EDTA (stock 500mM), final concentration 2nMTb-anti-p4E-BP1 antibody, 10mM EDTA.
1.3 test procedure:
1.3.1 Add 50. mu.L of a compound of the invention diluted in dimethyl sulfoxide (DMSO) at a concentration of 100. mu.M to a 38-well dilution plate.
1.3.2 Dilute the compound with dimethyl sulfoxide (DMSO) in a ratio of 1:3 (10 dilutions plus one zero concentration).
1.3.3 transfer 2.5. mu.L of the diluted compound (compound in Table 1) to the corresponding well (containing 47.5. mu.L of test solution per well) and shake for a few seconds.
1.3.4 Add 4. mu.L of mTOR working solution to 384-well black Proxi plates.
1.3.5 Add 2. mu.L of the diluted compound to the assay plate (3 wells per concentration).
1.3.6 incubate at room temperature for 15 minutes.
1.3.7 Add 4. mu.L of substrate working solution.
1.3.8 Final mTOR response concentration 0.3. mu.g/mL mTOR, 0.4. mu.M GFP-4E-BP1, 10. mu.M Adenosine Triphosphate (ATP). Compounds were diluted with 1% dimethyl sulfoxide (DMSO) to concentrations of 1. mu.M, 0.33. mu.M, 0.11. mu.M, 0.037. mu.M, 0.0123. mu.M, 0.00411. mu.M, 0.00137. mu.M, 0.000457. mu.M, 0.000152. mu.M, 0.000051. mu.M, 0. mu.M; .
1.3.9 incubate at room temperature for 30 minutes.
1.3.10 Add 10. mu.L of assay solution to the final working concentration Tb-anti-p4E-BP1 antibody 2nM, EDTA 10 mM.
1.3.11 were incubated at room temperature for 30 minutes.
1.3.12 readings for TR-FRET were detected using an Envision plate reader, excitation light was 340nm, emission 1 was 495nm, emission 2 was 520nm, the ratio 520nm/495nm was the TR-FRET value
1.3.13 data analysis and calculation of 50% inhibition (IC 50):
the 50% inhibition was calculated using the nonlinear regression equation:
y ═ bottom + (top-bottom)/(1 +10^ ((LogIC50-X) × HillSlope)), X: concentration of compound (logarithm to base 10), Y: TR-FRET value (ratio of 520nm to 495 nm), top and bottom: same high peak as Y (plateau in same units as Y), 50% inhibition (LogIC50): same logarithmic value as X (same logues as X). Table 1 shows the inhibitory activity of the mTOR enzyme.
CTG cell survival assay:
ATP is produced in living cell metabolic activity, and the content of ATP is linear with the number of living cells. The CTG chemiluminescence cell viability detection experiment is based on the principle and is a universal method for detecting the number of living cells in cultured cells. Addition of CellTiter-glo (CTG) reagent induces cell lysis and produces a chemiluminescent signal proportional to the amount of ATP in the well plate, which allows the viability of cell proliferation in the well plate to be measured by the chemiluminescent readout.
2.1 Experimental materials and instruments
2.1.1 Experimental materials: test compounds, cell basal Medium, RPMI Medium 1640(Invitrogen, Cat # 11875-: hyclone FETAL BOVINE SERUM DEFINED (Invitrogen, Cat # SH30070.03), antibiotics Penicilin Streptomyces (Invitrogen, Cat #15140-122), phosphate buffer (Corning Cellgro, Cat # R21-040-CV), cell digest: 0.25% Trypsin-EDTA (Invitrogen, Cat #25200-056), CTG assay kit: promega, Cat # G7571, 96-well flat-bottomed clear blackboard: NUNC, Cat #165305, T25 flasks: NUNC, Cat #156367, T75 flasks: NUNC, Cat #156439
2.2 Experimental apparatus: carbon dioxide incubator, SANYO-MCO-20AIC, biosafety cabinet: BSC-1360-LIIA2, bench top high speed refrigerated centrifuge: sorvalst 16R, microplate fast oscillator: QB-9001, M3 trigger reader: SpectraMax M3, microscope: OLYMPUS-CKX41/CKX 31.
2.3 solution and reagent preparation: preparation of a cell growth medium: RPMI Medium 1640+ 10% FBS + antibiotics, others: pancreatin digestive juice, Phosphate Buffer Solution (PBS), DMSO and CTG detection kit
2.4 Experimental procedure:
1.4.1 cell recovery: taking out the cryopreservation tube from the liquid nitrogen container, directly immersing the tube in water bath at 37 ℃, shaking the tube to melt the tube as soon as possible without any time, taking out the tube from the water bath at 37 ℃, transferring the tube to a biological safety cabinet, opening a cover, sucking out cell suspension by using a suction tube, adding the cell suspension into a centrifuge tube, dropwise adding more than 10 times of culture solution, and uniformly mixing; centrifuging at 1000rpm for 5 min; removing supernatant, adding cell growth culture medium-containing basic suspension cells, inoculating all cell suspensions to a T25 culture bottle, and standing and culturing in a 37 ℃ incubator; the culture solution was changed the next day and the culture was continued.
2.4.2 cell passages: when the cells grow to the logarithmic phase and the confluency is 80% -90%, taking out the cells to a biological safety cabinet, discarding the old culture solution, rinsing the cells for 1-2 times by PBS, adding a proper amount of 0.25% Trypsin-EDTA cell digestive juice into a culture bottle, placing the cells in a carbon dioxide incubator at 37 ℃ for 2-5min, adding a proper amount of cell growth culture medium containing 10% FBS to stop digestion, slightly blowing and beating the cells, transferring the cells to a centrifuge tube, centrifuging the cells at 1000rpm for 5min, preparing the cells into cell suspension, and then carrying out passage and experiment.
2.4.3 cell plating
2.4.3.1 preparation of cell suspension: when the cells grow to the logarithmic phase and the confluence ratio is 80% -90%, taking out the cells to a biological safety cabinet, discarding the old culture solution, rinsing the cells for 1-2 times by PBS, adding a proper amount of 0.25% Trypsin-EDTA cell digestive juice into a culture bottle, placing the cells in a carbon dioxide incubator at 37 ℃ for 2-5min, adding a proper amount of cell growth culture medium containing 10% FBS to stop digestion, lightly blowing, transferring the cells to a centrifuge tube, centrifuging at 1000rpm for 5min, counting, and adjusting the final concentration of the cell suspension to a proper concentration (the cell activity is more than 90%).
2.4.3.2 the cell suspension, adjusted to the final concentration, was added to a 96-well plate at 100ul per well.
2.4.3.3 was cultured at 37 ℃ in a 5% CO2 incubator for 24 h.
2.4.4 drug treatment
2.4.4.1 formulation of test compound stock solutions: test compound powders were dissolved in DMSO at a concentration of 10 mM.
2.4.4.2 gradient dilution formulation of test compound: first, 1ul of the test compound stock solution was added to 499ul of 10% FBS-containing cell growth medium, where the maximum concentration of test compound was 20uM and the DMSO concentration was 0.2%, and then 20uM of test compound was diluted 3-fold into 9 concentrations for a total of 10 concentration gradients in the cell growth medium containing 0.2% DMSO.
2.4.4.3 addition of test compound: dilutions of the test compound in the prepared gradient were added to the cell culture plate at 100ul per well, at a maximum concentration of 10uM test compound and a final concentration of 0.1% DMSO, in duplicate wells per concentration gradient, and blank control wells (containing 0.1% DMSO cell growth medium alone without cells) and negative control wells (cells and cell growth medium containing 1% DMSO) were set.
2.4.4.4 was allowed to act for 1 doubling time at 37 deg.C in a 5% CO2 incubator after the test compound was added.
2.4.5 detection and data analysis
2.4.5.1 detecting: the cell culture plate was removed, 100ul of medium was removed from each well and discarded, and the prepared CTG substrate was added to the plate at 50ul per well. Immediately oscillating on a microplate rapid oscillator for 2min after the addition is finished, then standing for 10min in a dark condition, balancing a luminescence signal, and reading the plate by a plate reader at M3.
2.4.5.2 data analysis: statistical analysis of the data was performed using GraphPad mapping software.
PI3K-alpha enzyme Activity assay: PI3K alpha-ADP Glo Assay was used. In the assay of PI3K enzyme activity, a test kit (Promega, cat # V9101) supplied by Promega was used to test the inhibitory effect of compounds on the activity of PI3K enzyme. The Adenosine Diphosphate (ADP) produced was quantified throughout the enzymatic reaction. The values obtained were used to calculate the activity of PI3K (table 1).
3.1 detection reagent: PIK3CA/PIK3R1, purchased from Invitrogen (cat # PV4788), was prepared by diluting the active kinase with kinase diluent III; mix with Bovine Serum Albumin (BSA) at a ratio of 1:4 (5 Xdilution) and the final BSA concentration is 50 ng/ml; composition of kinase assay solution I: 25mM MOPS, pH7.2, 12.5mM beta-glycerophosphate, 25mM magnesium chloride, 5mM EGTA, 2mM EDTA. Add 0.25mM DTT to 250. mu.M Adenosine Triphosphate (ATP) in kinase assay solution I before use; detection liquid: 0.55mg of ATP was dissolved in 4ml of kinase assay solution I, dispensed 200. mu.l per tube and stored at-20 ℃. Substrate: phosphatidylinositol (4,5) diphosphate [ phospholambydilingositol (4,5) bis-phosphate ]; the substrate was diluted to 125. mu.M with kinase assay solution I. The final concentration was: 10M PIP2,10M ATP, 1% DMSO,0.0005-10M compound.
a) The test steps are as follows:
3.2.1 Add 50. mu.L of compound diluted in dimethyl sulfoxide (DMSO) at a concentration of 100. mu.M to 384 well dilution plates. Compounds were diluted with dimethyl sulfoxide (DMSO) at a ratio of 1:3 (10 dilutions plus one zero concentration).
3.2.2 transfer 5. mu.L of the diluted compound to the corresponding 384-well black Proxi plate (containing 47.5. mu.L of assay per well) and shake for a few seconds.
3.2.3 Add 2. mu.L of 2.5xPI3K working solution to 384-well black Proxi plates.
3.2.4 Add 2. mu.L of the diluted compound to the assay plate (3 wells per concentration).
3.2.5 were incubated at room temperature for 2 hours.
3.2.6 Add 5. mu.L ADP Glo reagent
3.2.7 incubate at room temperature for 40 minutes.
3.2.8 mu.L of kinase detection reagent was added.
3.2.9 were incubated at room temperature for 40 minutes.
3.2.10 were tested using an Envision trigger reader.
3.3 analysis of data and calculation of 50% inhibition (IC 50): IC calculation Using Prism5 software50The results show that the compounds of the present application have inhibitory effects on the activity of mTOR protease. The mTOR protease activity inhibition range of the compounds is 0.5-several hundred nanomolar, see table 1. The measured inhibition of PI3K enzyme activity is shown in table 2. The data for the tumor cell line inhibition determined are shown in table 1. These data show that the compounds of the present application have the activity of inhibiting mTOR, PI3K protease, and also have antitumor activity.
TABLE 1 cellular Activity and mTOR protease Activity of Compounds of the present application
Table 2: compounds inhibit PI3K enzyme activity
4. Pharmacokinetic characteristics:
4.1 animal testing
The test compounds were administered orally to mice and their bioavailability and pharmacokinetic profile in the plasma of the mice were determined.
4.2 test methods:
the administration route is as follows: gavage (PO) at a dose of 10mg/kg, a final concentration of 1mg/mL, and a volume of 10 mL/kg.
4.3 Whole blood sample Collection: blood was taken from the animals at approximately 300. mu.L each time. Blood was taken once before administration, 0.25 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours and 24 hours after administration. The collected blood samples were centrifuged at 2000rpm for 5min at 4 ℃ to obtain plasma which was transferred to a polyethylene microfuge tube and stored in a refrigerator at-80 ℃.
4.4 biological sample analysis method
LC/MS/MS biological sample analysis method
4.5 test results
The highest concentration of test compound in animals, half-life and six hour compound concentration in blood and AUC (table 3).
TABLE 3 murine pharmacokinetic data (oral 10mg/kg)
5. And (3) testing the solubility:
table 4. examples of the solubility of the compounds of the present application in common aqueous vehicles (25 ℃, pH 3):
examples Solvent Solubility in water
1 Water (W) >1mg/ml
18 Water (W) >5mg/ml
19 30% hydroxypropyl- β -cyclodextrin >1mg/ml
28 30% sulfobutyl- β -cyclodextrin >3mg/ml
31 Water (W) >5mg/ml
52 Water (W) >1mg/ml

Claims (7)

1. A compound represented by formula I, a pharmaceutically acceptable salt, stereoisomer, or isotopic label thereof:
wherein,
ring a and ring B are independently selected from pyrazolyl, pyridinyl, phenyl or triazolyl;
ring C is cyclopentyl or cyclohexyl attached to one heteroatom, or is a saturated 4-6 membered heterocyclic ring containing at least one heteroatom selected from N or O;
R1is at least one group connecting ring C, selected from phenyl-substituted C1-3An alkyl group; or is selected from R6CO-、R6SO2-、R6CONH-or R6SO2NH-, in which R6Is selected from-NH2Methyl, ethyl, triazolyl or cyclopropyl;
R2selected from H, methyl, ethyl, n-propyl or isopropyl;
R3selected from H, methyl, ethyl, n-propyl or isopropyl;
R4is at least one group connecting ring a independently selected from H, methyl, ethyl, n-propyl or isopropyl;
x is selected from CH or N.
2. A compound, pharmaceutically acceptable salt, stereoisomer or isotopic label thereof according to claim 1, wherein ring a is selected from pyrazolyl, pyridinyl, phenyl or triazolyl, and ring B is selected from pyrazolyl or pyridinyl; ring C is selected from cyclopentyl, cyclohexyl, azetidinyl, piperidinyl, or pyrrolidinyl;
R2selected from H or methyl;
R3selected from H or methyl;
R4selected from H or methyl.
3. A compound, a pharmaceutically acceptable salt, a stereoisomer, or an isotopic label thereof, wherein the compound is selected from the group consisting of:
1- (1- (2-hydroxyacetyl) piperidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- (1- (1H-1,2, 4-triazole-3-carbonyl) piperidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) piperidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- (1- ((S) -2-hydroxypropionyl) piperidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- (1- ((R) -2-hydroxypropionyl) piperidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- (1- (2-hydroxyacetyl) pyrrolidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- (1- (1H-1,2, 4-triazole-3-carbonyl) pyrrolidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1-methylpyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- (1-ethylpyrrolidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- (1-acetylpyrrolidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- (1-Benzylpyrrolidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- (1- ((4-chlorophenyl) sulfonyl) pyrrolidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1-p-toluenesulfonylpyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
3- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) pyrrolidine-1-sulfonamide
3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (2,2, 2-trifluoroacetyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- ((1r,4r) -4-hydroxycyclohexyl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- ((1s,4s) -4-hydroxycyclohexyl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- ((1s,4s) -4-hydroxycyclohexyl) -3-methyl-8- (6-phenylpyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- ((1s,4s) -4-hydroxycyclohexyl) -3-methyl-8- (1-phenyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- ((1r,4r) -4-hydroxycyclohexyl) -3-methyl-8- (1-phenyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- ((1r,4r) -4-hydroxycyclohexyl) -3-methyl-8- (6-phenylpyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(R) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(S) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(S) -1- (1- (ethylsulfonyl) pyrrolidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(S) -3-methyl-1- (1- (methylsulfonyl) pyrrolidin-3-yl) -8- (6-phenylpyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(R) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) piperidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- (3-hydroxycyclohexyl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
N- ((1s,4s) -4- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) cyclohexanyl) acetamide
N- ((1s,4s) -4- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) cyclohexyl) methanesulfonamide
(1s,4s) -4- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) cyclohexanecarboxylic acid
3-deuterated methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) piperidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) piperidin-3-yl) -1H-imidazo [4,5-c ] [1,5] naphthyridin-2 (3H) -one
(S) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c ] [1,5] naphthyridin-2 (3H) -one
(S) -3-methyl-1- (1- (methylsulfonyl) pyrrolidin-3-yl) -8- (6-phenylpyridin-3-yl) -1H-imidazo [4,5-c ] [1,5] naphthyridin-2 (3H) -one.
2-methyl-2- (4- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) phenyl) propionamide
2-methyl-2- (4- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) phenyl) propanoic acid
1- (3-Hydroxycyclopentyl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(S) -8- (6- (1H-1,2, 4-triazol-1-yl) pyridin-3-yl) -3-methyl-1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(S) -8- (6- (1H-pyrazol-1-yl) pyridin-3-yl) -3-methyl-1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(S) -3-methyl-8- (6- (1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(S) -8- (6- (1H-1,2, 3-triazol-1-yl) pyridin-3-yl) -3-methyl-1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(S) -3-methyl-8- (6- (1-methyl-1H-pyrazol-3-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(S) -3-methyl-8- (6- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(R) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) piperidin-3-yl) -1H-imidazo [4,5-c ] [1,5] naphthyridin-2 (3H) -one
(S) -3-methyl-8- (6- (1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-imidazo [4,5-c ] [1,5] naphthyridin-2 (3H) -one
1- ((1s,4s) -4-hydroxycyclohexyl) -3-methyl-8- (6- (1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(R) -1- (1- (ethylsulfonyl) piperidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(R) -1- (1- (cyclopropylsulfonyl) piperidin-3-yl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(R) -3- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) piperidine-1-sulfonamide
(R) -N-ethyl-3- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) piperidine-1-carboxamide
(R) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- ((trifluoromethyl) sulfonyl) piperidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
1- (4-hydroxy-4-methylcyclohexyl) -3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
(R) -3-methyl-8- (6- (1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) piperidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) piperidin-4-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
3-methyl-8- (6- (1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) piperidin-4-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
3-methyl-8- (6- (1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) -1- (8- (methylsulfonyl) -8-azabicyclo [3.2.1] octan-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (8- (methylsulfonyl) -8-azabicyclo [3.2.1] octan-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one
N- (2- (3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) ethyl) methanesulfonamide
3-methyl-8- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1- (1- (methylsulfonyl) azetidin-3-yl) -1H-imidazo [4,5-c ] quinolin-2 (3H) -one.
4. A pharmaceutical composition comprising a compound of any one of claims 1-3, a pharmaceutically acceptable salt, stereoisomer, or isotopic label thereof, and a pharmaceutically acceptable carrier.
5. Use of a compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt, stereoisomer or isotopic label thereof, in the manufacture of a medicament for inhibiting one or both of mTOR and PI3K kinase.
6. Use of a compound of any one of claims 1-3, a pharmaceutically acceptable salt, stereoisomer, or isotopic label thereof in the manufacture of a medicament for treating or preventing a disorder selected from at least one of cancer, a metabolic disorder, and a cardiovascular disorder.
7. The use according to claim 6, wherein the metabolic disease is selected from at least one of diabetes and obesity.
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US11919899B2 (en) 2020-09-21 2024-03-05 Wei Zhong Substituted 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-c] quinolin-2-one compounds with blood-brain barrier penetrable capability
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102372711A (en) * 2010-08-18 2012-03-14 山东轩竹医药科技有限公司 Imidazo quinoline PI3K and mTOR (mammalian target of rapamycin) dual inhibitor
CN102399218A (en) * 2010-09-16 2012-04-04 和记黄埔医药（上海）有限公司 Triheterocyclic compounds and their use as PI3K inhibitors

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2129379B1 (en) 2007-02-20 2019-04-10 Novartis AG Imidazoquinolines as dual lipid kinase and mtor inhibitors
US8791131B2 (en) 2008-09-30 2014-07-29 Pfizer Inc. Imidazo[1,5]naphthyridine compounds, their pharmaceutical use and compositions
US8476294B2 (en) 2009-06-04 2013-07-02 Novartis Ag 1H-imidazo[4,5-c]quinolinone derivatives
EP2475375A4 (en) 2009-09-09 2013-02-20 Avila Therapeutics Inc Pi3 kinase inhibitors and uses thereof
CA2819955A1 (en) * 2010-12-06 2012-06-14 Piramal Enterprises Limited Substituted imidazoquinoline derivatives
CN103833752A (en) 2012-11-20 2014-06-04 北京富龙康泰生物技术有限公司 Imidazolone quinoline derivatives, and medicinal composition and use thereof
AU2014352463B2 (en) 2013-11-20 2017-05-11 Beijing Forelandpharma Co. Ltd. Ketone derivatives of imidazoles, pharmaceutical combinations and uses thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102372711A (en) * 2010-08-18 2012-03-14 山东轩竹医药科技有限公司 Imidazo quinoline PI3K and mTOR (mammalian target of rapamycin) dual inhibitor
CN102399218A (en) * 2010-09-16 2012-04-04 和记黄埔医药（上海）有限公司 Triheterocyclic compounds and their use as PI3K inhibitors

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